Evolution on neutral networks accelerates the ticking rate of the molecular clock

Large sets of genotypes give rise to the same phenotype, because phenotypic expression is highly redundant. Accordingly, a population can accept mutations without altering its phenotype, as long as the genotype mutates into another one on the same set. By linking every pair of genotypes that are mutually accessible through mutation, genotypes organize themselves into neutral networks (NNs). These networks are known to be heterogeneous and assortative, and these properties affect the evolutionary dynamics of the population. By studying the dynamics of populations on NNs with arbitrary topology, we analyse the effect of assortativity, of NN (phenotype) fitness and of network size. We find that the probability that the population leaves the network is smaller the longer the time spent on it. This progressive ‘phenotypic entrapment’ entails a systematic increase in the overdispersion of the process with time and an acceleration in the fixation rate of neutral mutations. We also quantify the variation of these effects with the size of the phenotype and with its fitness relative to that of neighbouring alternatives.

[1]  P. Schuster,et al.  From sequences to shapes and back: a case study in RNA secondary structures , 1994, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[2]  C. Wilke,et al.  Thermodynamics of Neutral Protein Evolution , 2006, Genetics.

[3]  Giovanni Marco Dall'Olio,et al.  Human Genome Variation and the Concept of Genotype Networks , 2013, PloS one.

[4]  M. Huynen,et al.  Neutral evolution of mutational robustness. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Samuel Karlin,et al.  A First Course on Stochastic Processes , 1968 .

[6]  Andreas Wagner,et al.  Neutral network sizes of biological RNA molecules can be computed and are not atypically small , 2008, BMC Bioinformatics.

[7]  M. Kimura Evolutionary Rate at the Molecular Level , 1968, Nature.

[8]  N. Wingreen,et al.  Emergence of Preferred Structures in a Simple Model of Protein Folding , 1996, Science.

[9]  C. Wilke Molecular clock in neutral protein evolution , 2004, BMC Genetics.

[10]  Tosio Kato Perturbation theory for linear operators , 1966 .

[11]  Michele Vendruscolo,et al.  Neutral evolution of model proteins: diffusion in sequence space and overdispersion. , 1998, Journal of theoretical biology.

[12]  P. Lio’,et al.  Models of molecular evolution and phylogeny. , 1998, Genome research.

[13]  N. Takahata,et al.  On the overdispersed molecular clock. , 1987, Genetics.

[14]  J. Gillespie The causes of molecular evolution , 1991 .

[15]  P. Schuster,et al.  Analysis of RNA sequence structure maps by exhaustive enumeration I. Neutral networks , 1995 .

[16]  Javier M Buldú,et al.  Evolutionary dynamics on networks of selectively neutral genotypes: effects of topology and sequence stability. , 2009, Physical review. E, Statistical, nonlinear, and soft matter physics.

[17]  Javier M. Buldú,et al.  Correction: Topological Structure of the Space of Phenotypes: The Case of RNA Neutral Networks , 2011, PLoS ONE.

[18]  Andreas Wagner,et al.  Evolutionary Plasticity and Innovations in Complex Metabolic Reaction Networks , 2009, PLoS Comput. Biol..

[19]  R. Sanjuán,et al.  Selection for thermostability can lead to the emergence of mutational robustness in an RNA virus , 2010, Journal of evolutionary biology.

[20]  D. Lipman,et al.  Modelling neutral and selective evolution of protein folding , 1991, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[21]  Gergely J Szöllosi,et al.  The effect of recombination on the neutral evolution of genetic robustness. , 2008, Mathematical biosciences.

[22]  Gergely J Szöllosi,et al.  Congruent evolution of genetic and environmental robustness in micro-RNA. , 2008, Molecular biology and evolution.

[23]  A. Wagner,et al.  The origins of evolutionary innovation , 2010 .

[24]  A. Wagner,et al.  Innovation and robustness in complex regulatory gene networks , 2007, Proceedings of the National Academy of Sciences.

[25]  E. Bornberg-Bauer,et al.  Modeling evolutionary landscapes: mutational stability, topology, and superfunnels in sequence space. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  A. Baker,et al.  A mitogenomic timescale for birds detects variable phylogenetic rates of molecular evolution and refutes the standard molecular clock. , 2006, Molecular biology and evolution.

[27]  S. Elena,et al.  In silico predicted robustness of viroids RNA secondary structures. I. The effect of single mutations. , 2006, Molecular biology and evolution.

[28]  A. Rodrigo,et al.  Time‐dependent rates of molecular evolution , 2011, Molecular ecology.

[29]  Alpan Raval,et al.  Molecular clock on a neutral network. , 2007, Physical review letters.

[30]  Sudhir Kumar,et al.  Molecular clocks: four decades of evolution , 2005, Nature Reviews Genetics.

[31]  S. Manrubia,et al.  On the structural repertoire of pools of short, random RNA sequences. , 2008, Journal of theoretical biology.

[32]  Joshua B. Plotkin,et al.  The Origins of Evolutionary Innovations , 2012 .

[33]  Trevor Bedford,et al.  Overdispersion of the molecular clock: temporal variation of gene-specific substitution rates in Drosophila. , 2008, Molecular biology and evolution.

[34]  W. Ewens Mathematical Population Genetics , 1980 .

[35]  Rafael Sanjuán,et al.  Shape Matters: Effect of Point mutations on RNA secondary Structure , 2013, Adv. Complex Syst..

[36]  John Maynard Smith,et al.  Natural Selection and the Concept of a Protein Space , 1970, Nature.

[37]  O. Martin,et al.  Neutral Network Sizes of Biological RNA Molecules Can Be Computed and Are Atypically Large , 2022 .

[38]  Iain G. Johnston,et al.  A tractable genotype–phenotype map modelling the self-assembly of protein quaternary structure , 2014, Journal of The Royal Society Interface.

[39]  S. Feld Why Your Friends Have More Friends Than You Do , 1991, American Journal of Sociology.

[40]  T. Ohta,et al.  On the rate of molecular evolution , 2005, Journal of Molecular Evolution.

[41]  Markus Porto,et al.  Connectivity of Neutral Networks, Overdispersion, and Structural Conservation in Protein Evolution , 2001, Journal of Molecular Evolution.

[42]  L. Pauling,et al.  Evolutionary Divergence and Convergence in Proteins , 1965 .

[43]  J. Draghi,et al.  Epistasis Increases the Rate of Conditionally Neutral Substitution in an Adapting Population , 2011, Genetics.

[44]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[45]  P. Schuster,et al.  Complete suboptimal folding of RNA and the stability of secondary structures. , 1999, Biopolymers.

[46]  J H Gillespie,et al.  The molecular clock may be an episodic clock. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Charles H. Langley,et al.  An examination of the constancy of the rate of molecular evolution , 2005, Journal of Molecular Evolution.