From genotypes to organisms: State-of-the-art and perspectives of a cornerstone in evolutionary dynamics.

Understanding how genotypes map onto phenotypes, fitness, and eventually organisms is arguably the next major missing piece in a fully predictive theory of evolution. Though we are still far from achieving a complete picture of these relationships, our current understanding of simpler questions, such as the structure induced in the space of genotypes by sequences mapped to molecular structures (the so-called genotype-phenotype map), has revealed important facts that deeply affect the dynamical description of evolutionary processes. Empirical evidence supporting the fundamental relevance of features such as phenotypic bias is mounting as well, while the synthesis of conceptual and experimental progress leads to questioning current assumptions on the nature of evolutionary dynamics---cancer progression models or synthetic biology approaches being notable examples. This work delves into a critical and constructive attitude in our current knowledge of how genotypes map onto molecular phenotypes and organismal functions, and discusses theoretical and empirical avenues to broaden and improve this comprehension. As a final goal, this community should aim at deriving an updated picture of evolutionary processes soundly relying on the structural properties of genotype spaces, as revealed by modern techniques of molecular and functional analysis.

[1]  A. Wagner Robustness and Evolvability in Living Systems , 2005 .

[2]  Neo D. Martinez,et al.  Approaching a state shift in Earth’s biosphere , 2012, Nature.

[3]  Joachim Krug,et al.  Unraveling the causes of adaptive benefits of synonymous mutations in TEM-1 β-lactamase , 2018, Heredity.

[4]  Nicholas C. Wu,et al.  A Comprehensive Biophysical Description of Pairwise Epistasis throughout an Entire Protein Domain , 2014, Current Biology.

[5]  Ville Mustonen,et al.  Energy-dependent fitness: A quantitative model for the evolution of yeast transcription factor binding sites , 2008, Proceedings of the National Academy of Sciences.

[6]  Nigel F. Delaney,et al.  Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins , 2006, Science.

[7]  T. Dobzhansky Studies on Hybrid Sterility. II. Localization of Sterility Factors in Drosophila Pseudoobscura Hybrids. , 1936, Genetics.

[8]  Bhavin S. Khatri Survival of the frequent at finite population size and mutation rate: filing the gap between quasispecies and monomorphic regimes , 2018 .

[9]  N. Johnson,et al.  Rapid speciation via parallel, directional selection on regulatory genetic pathways. , 2000, Journal of theoretical biology.

[10]  Hao Li,et al.  Designability of protein structures: A lattice‐model study using the Miyazawa‐Jernigan matrix , 2002, Proteins.

[11]  Frank J. Poelwijk,et al.  The Context-Dependence of Mutations: A Linkage of Formalisms , 2015, PLoS Comput. Biol..

[12]  M. Conrad Bootstrapping on the adaptive landscape. , 1979, Bio Systems.

[13]  Feng Jiang,et al.  Inferring Tree Models for Oncogenesis from Comparative Genome Hybridization Data , 1999, J. Comput. Biol..

[14]  G. Church,et al.  Large-scale de novo DNA synthesis: technologies and applications , 2014, Nature Methods.

[15]  Andreas Wagner,et al.  Adding levels of complexity enhances robustness and evolvability in a multilevel genotype–phenotype map , 2017, Journal of The Royal Society Interface.

[16]  Kamaludin Dingle,et al.  The structure of the genotype–phenotype map strongly constrains the evolution of non-coding RNA , 2015, Interface Focus.

[17]  Gaurav Sablok,et al.  Expression properties exhibit correlated patterns with the fate of duplicated genes, their divergence, and transcriptional plasticity in Saccharomycotina , 2017, DNA research : an international journal for rapid publication of reports on genes and genomes.

[18]  Jack Kuipers,et al.  Large-scale inference of conjunctive Bayesian networks , 2016, Bioinform..

[19]  A. Force,et al.  Preservation of duplicate genes by complementary, degenerative mutations. , 1999, Genetics.

[20]  R. Goldstein,et al.  The evolution and evolutionary consequences of marginal thermostability in proteins , 2011, Proteins.

[21]  Bonnie Berger,et al.  Inverting the Viterbi algorithm: an abstract framework for structure design , 2008, ICML '08.

[22]  Andrew D Ellington,et al.  Synthetic DNA Synthesis and Assembly: Putting the Synthetic in Synthetic Biology. , 2017, Cold Spring Harbor perspectives in biology.

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

[24]  Michael Conrad The importance of molecular hierarchy In Information processing , 2017 .

[25]  Remy Chait,et al.  Evolutionary paths to antibiotic resistance under dynamically sustained drug selection , 2011, Nature Genetics.

[26]  N. Barton,et al.  The infinitesimal model: Definition, derivation, and implications. , 2017, Theoretical population biology.

[27]  Debora S Marks,et al.  Deep generative models of genetic variation capture the effects of mutations , 2018, Nature Methods.

[28]  J. DeGregori,et al.  Adaptive Oncogenesis: A New Understanding of How Cancer Evolves inside Us , 2018 .

[29]  Ryan T Gill,et al.  Deep scanning lysine metabolism in Escherichia coli , 2018, Molecular systems biology.

[30]  Pablo Catalán Fernández Models in molecular evolution: the case of toyLIFE , 2017 .

[31]  A. Stoltzfus On the Possibility of Constructive Neutral Evolution , 1999, Journal of Molecular Evolution.

[32]  Feng Ding,et al.  Protein folding: then and now. , 2008, Archives of biochemistry and biophysics.

[33]  Nicholas Eriksson,et al.  The Temporal Order of Genetic and Pathway Alterations in Tumorigenesis , 2011, PloS one.

[34]  Norman A. Johnson,et al.  Toward a new synthesis: population genetics and evolutionary developmental biology , 2004, Genetica.

[35]  Joshua D. Knowles,et al.  Analysis of a complete DNA–protein affinity landscape , 2010, Journal of The Royal Society Interface.

[36]  P. Schuster,et al.  Shaping space: the possible and the attainable in RNA genotype-phenotype mapping. , 1998, Journal of theoretical biology.

[37]  Andreas Wagner,et al.  Exhaustive Analysis of a Genotype Space Comprising 1015 Central Carbon Metabolisms Reveals an Organization Conducive to Metabolic Innovation , 2015, PLoS Comput. Biol..

[38]  Gregory W. Campbell,et al.  Comprehensive experimental fitness landscape and evolutionary network for small RNA , 2013, Proceedings of the National Academy of Sciences.

[39]  Niko Beerenwinkel,et al.  Estimating the predictability of cancer evolution , 2019, Bioinform..

[40]  J. Krug,et al.  Diminishing-returns epistasis among random beneficial mutations in a multicellular fungus , 2016, Proceedings of the Royal Society B: Biological Sciences.

[41]  W. Fontana Modelling 'evo-devo' with RNA. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[42]  Zhen Li,et al.  Gene Duplicability of Core Genes Is Highly Consistent across All Angiosperms[OPEN] , 2016, Plant Cell.

[43]  P. Schuster,et al.  Generic properties of combinatory maps: neutral networks of RNA secondary structures. , 1997, Bulletin of mathematical biology.

[44]  M. Nachman,et al.  Estimate of the mutation rate per nucleotide in humans. , 2000, Genetics.

[45]  Bor-Sen Chen,et al.  Robust Design of Biological Circuits: Evolutionary Systems Biology Approach , 2011, Journal of biomedicine & biotechnology.

[46]  S. Fields,et al.  Deep mutational scanning: a new style of protein science , 2014, Nature Methods.

[47]  Santiago F. Elena,et al.  Distribution of Fitness and Virulence Effects Caused by Single-Nucleotide Substitutions in Tobacco Etch Virus , 2007, Journal of Virology.

[48]  Vivek K. Mutalik,et al.  Composability of regulatory sequences controlling transcription and translation in Escherichia coli , 2013, Proceedings of the National Academy of Sciences.

[49]  Herbert M Sauro,et al.  Visualization of evolutionary stability dynamics and competitive fitness of Escherichia coli engineered with randomized multigene circuits. , 2013, ACS synthetic biology.

[50]  Giancarlo Mauri,et al.  Algorithmic methods to infer the evolutionary trajectories in cancer progression , 2015, Proceedings of the National Academy of Sciences.

[51]  D. Bartel,et al.  One sequence, two ribozymes: implications for the emergence of new ribozyme folds. , 2000, Science.

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

[53]  Joachim Krug,et al.  Genotypic Complexity of Fisher’s Geometric Model , 2016, Genetics.

[54]  Richard A. Goldstein,et al.  Biophysics and population size constrains speciation in an evolutionary model of developmental system drift , 2019, PLoS Comput. Biol..

[55]  George M. Church,et al.  Beyond editing to writing large genomes , 2017, Nature Reviews Genetics.

[56]  Paulien Hogeweg,et al.  Evolution of Functional Diversification within Quasispecies , 2014, Genome biology and evolution.

[57]  A. Ferré-D’Amaré,et al.  Rapid Construction of Empirical RNA Fitness Landscapes , 2010, Science.

[58]  Peter Clote,et al.  Complete RNA inverse folding: computational design of functional hammerhead ribozymes , 2014, Nucleic acids research.

[59]  M. Lässig,et al.  From fitness landscapes to seascapes: non-equilibrium dynamics of selection and adaptation. , 2009, Trends in genetics : TIG.

[60]  N. Jojic,et al.  Deep learning of the regulatory grammar of yeast 5′ untranslated regions from 500,000 random sequences , 2017, bioRxiv.

[61]  Santiago F. Elena,et al.  Epistasis between mutations is host-dependent for an RNA virus , 2013, Biology Letters.

[62]  S. Nee,et al.  INFERRING SPECIATION RATES FROM PHYLOGENIES , 2001, Evolution; international journal of organic evolution.

[63]  Paul B Rainey,et al.  Experimental evolution reveals hidden diversity in evolutionary pathways , 2015, eLife.

[64]  Thomas E Gorochowski,et al.  DNAplotlib: Programmable Visualization of Genetic Designs and Associated Data. , 2017, ACS synthetic biology.

[65]  Jason H. Moore,et al.  Robustness, Evolvability, and the Logic of Genetic Regulation , 2014, Artificial Life.

[66]  Michael Stich,et al.  The dawn of the RNA World: toward functional complexity through ligation of random RNA oligomers. , 2009, RNA.

[67]  O. Tenaillon,et al.  Properties of selected mutations and genotypic landscapes under Fisher's geometric model , 2014, Evolution; international journal of organic evolution.

[68]  Paulien Hogeweg,et al.  Evolution of complexity in RNA-like replicator systems , 2008, Biology Direct.

[69]  A. Wagner Mutational robustness accelerates the origin of novel RNA phenotypes through phenotypic plasticity. , 2014, Biophysical journal.

[70]  Arlin Stoltzfus,et al.  Modeling Evolution Using the Probability of Fixation: History and Implications , 2014, The Quarterly Review of Biology.

[71]  P. Hogeweg,et al.  Evolutionary Conflict Leads to Innovation: Symmetry Breaking in a Spatial Model of RNA-Like Replicators , 2017, Life.

[72]  Ben Lehner,et al.  The genetic landscape of a physical interaction , 2018, eLife.

[73]  F Armadá Maresca,et al.  [History of evolution]. , 2005, Archivos de la Sociedad Espanola de Oftalmologia.

[74]  Dmitry Chudakov,et al.  Local fitness landscape of the green fluorescent protein , 2016, Nature.

[75]  Peter Clote,et al.  RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory , 2016, BMC Bioinformatics.

[76]  Adam J. Meyer,et al.  Hachimoji DNA and RNA: A genetic system with eight building blocks , 2019, Science.

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

[78]  C. Petropoulos,et al.  Evidence for Positive Epistasis in HIV-1 , 2004, Science.

[79]  D. Haussler,et al.  Evolution's cauldron: Duplication, deletion, and rearrangement in the mouse and human genomes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Meredith V. Trotter,et al.  Robustness and evolvability. , 2010, Trends in genetics : TIG.

[81]  W. Fontana,et al.  Plasticity, evolvability, and modularity in RNA. , 2000, The Journal of experimental zoology.

[82]  Susanna Manrubia,et al.  The space of genotypes is a network of networks: implications for evolutionary and extinction dynamics , 2017, Scientific Reports.

[83]  Sebastian E. Ahnert,et al.  Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability , 2015, PLoS Comput. Biol..

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

[85]  L. Altenberg EMERGENT PHENOMENA IN GENETIC PROGRAMMING , 1994 .

[86]  Rafael Sanjuán,et al.  Quantifying antagonistic epistasis in a multifunctional RNA secondary structure of the Rous sarcoma virus. , 2006, The Journal of general virology.

[87]  Carl Troein,et al.  Mutation-induced fold switching among lattice proteins. , 2011, The Journal of chemical physics.

[88]  Giancarlo Mauri,et al.  CAPRI: Efficient Inference of Cancer Progression Models from Cross-sectional Data , 2014, bioRxiv.

[89]  Mason A. Porter,et al.  Multilayer networks , 2013, J. Complex Networks.

[90]  Elizabeth Quill,et al.  When networks network: Once studied solo, systems display surprising behavior when they interact , 2012 .

[91]  H. P. de Vladar,et al.  Statistical Mechanics and the Evolution of Polygenic Quantitative Traits , 2009, Genetics.

[92]  Hsuan-Cheng Huang,et al.  Dissecting the Human Protein-Protein Interaction Network via Phylogenetic Decomposition , 2014, Scientific Reports.

[93]  Susanna Manrubia,et al.  On the networked architecture of genotype spaces and its critical effects on molecular evolution , 2018, Open Biology.

[94]  Alan C. Love Conceptual Change in Biology , 2015 .

[95]  S. Carpenter,et al.  Catastrophic shifts in ecosystems , 2001, Nature.

[96]  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.

[97]  Christopher A. Voigt,et al.  Principles of genetic circuit design , 2014, Nature Methods.

[98]  L. Altenberg The evolution of evolvability in genetic programming , 1994 .

[99]  Ramón Díaz-Uriarte,et al.  Cancer progression models and fitness landscapes: a many-to-many relationship , 2017, bioRxiv.

[100]  Angus M. Sidore,et al.  Multiplexed Gene Synthesis in Emulsions for Exploring Protein Functional Landscapes , 2017 .

[101]  Sasha F. Levy,et al.  Development of a Comprehensive Genotype-to-Fitness Map of Adaptation-Driving Mutations in Yeast , 2016, Cell.

[102]  R Sevilla-Escoboza,et al.  Synchronization of interconnected networks: the role of connector nodes. , 2014, Physical review letters.

[103]  Liam Kemp,et al.  This wonderful life , 2003, SVR '03.

[104]  Andreas Wagner,et al.  Protein robustness promotes evolutionary innovations on large evolutionary time-scales , 2008, Proceedings of the Royal Society B: Biological Sciences.

[105]  Manjunatha Kogenaru,et al.  Multiple peaks and reciprocal sign epistasis in an empirically determined genotype-phenotype landscape. , 2010, Chaos.

[106]  G. Wagner,et al.  Evolution of Evolvability in a Developmental Model , 2008, Evolution; international journal of organic evolution.

[107]  J. Valcárcel,et al.  The complete local genotype–phenotype landscape for the alternative splicing of a human exon , 2016, Nature Communications.

[108]  Anton Crombach,et al.  Chromosome rearrangements and the evolution of genome structuring and adaptability. , 2007, Molecular biology and evolution.

[109]  S. Ahnert,et al.  A tractable genotype-phenotype map for the self-assembly of protein quaternary structure , 2013, 1311.0399.

[110]  Nir Friedman,et al.  Deciphering eukaryotic gene-regulatory logic with 100 million random promoters , 2019, Nature Biotechnology.

[111]  S. Carpenter,et al.  Anticipating Critical Transitions , 2012, Science.

[112]  Hanna Kokko,et al.  Searching for a Cancer-Proof Organism: It’s the Journey That Teaches You About the Destination , 2017 .

[113]  Per Kristian Lehre,et al.  Accessibility between neutral networks in indirect genotype-phenotype mappings , 2005, 2005 IEEE Congress on Evolutionary Computation.

[114]  M. Huynen,et al.  Pattern generation in molecular evolution: Exploitation of the variation in RNA landscapes , 1994, Journal of Molecular Evolution.

[115]  D. J. Kiviet,et al.  Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes. , 2011, Journal of theoretical biology.

[116]  S. Elena,et al.  Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus , 2012, Heredity.

[117]  Jianzhi Zhang,et al.  Multi-environment fitness landscapes of a tRNA gene , 2018, Nature Ecology & Evolution.

[118]  Nigel F. Delaney,et al.  Diminishing Returns Epistasis Among Beneficial Mutations Decelerates Adaptation , 2011, Science.

[119]  Richard A. Goldstein,et al.  Simple Biophysical Model Predicts Faster Accumulation of Hybrid Incompatibilities in Small Populations Under Stabilizing Selection , 2015, Genetics.

[120]  Udayan Mohanty,et al.  Compact and ordered collapse of randomly generated RNA sequences , 2005, Nature Structural &Molecular Biology.

[121]  D. Schluter,et al.  Does evolutionary theory need a rethink? , 2014, Nature.

[122]  Andreas Wagner,et al.  Genotype networks in metabolic reaction spaces , 2010, BMC Systems Biology.

[123]  A. Kondrashov,et al.  Multidimensional epistasis and the disadvantage of sex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Rafael Sanjuán,et al.  The contribution of epistasis to the architecture of fitness in an RNA virus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[125]  R H Borts,et al.  Direct estimate of the mutation rate and the distribution of fitness effects in the yeast Saccharomyces cerevisiae. , 2001, Genetics.

[126]  R. Punnett,et al.  The Genetical Theory of Natural Selection , 1930, Nature.

[127]  R. Jensen Enzyme recruitment in evolution of new function. , 1976, Annual review of microbiology.

[128]  G. Wagner,et al.  EVOLUTION AND DETECTION OF GENETIC ROBUSTNESS , 2003 .

[129]  David Alvarez-Ponce,et al.  Intrinsic protein disorder reduces small-scale gene duplicability , 2017, DNA research : an international journal for rapid publication of reports on genes and genomes.

[130]  Eugene V Koonin,et al.  The Biological Big Bang model for the major transitions in evolution , 2007, Biology Direct.

[131]  Claude Thermes,et al.  The Third Revolution in Sequencing Technology. , 2018, Trends in genetics : TIG.

[132]  Raul Andino,et al.  Mutational and fitness landscapes of an RNA virus revealed through population sequencing , 2013, Nature.

[133]  C. Ofria,et al.  Evolution of digital organisms at high mutation rates leads to survival of the flattest , 2001, Nature.

[134]  Ricardo Flores,et al.  Origin and Evolution of Viroids , 2017 .

[135]  Sebastian E Ahnert,et al.  Phenotypes can be robust and evolvable if mutations have non-local effects on sequence constraints , 2018, Journal of The Royal Society Interface.

[136]  Ting Hu,et al.  The Effects of Recombination on Phenotypic Exploration and Robustness in Evolution , 2014, Artificial Life.

[137]  V. Shahrezaei,et al.  Protein ground state candidates in a simple model: an enumeration study. , 1999, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[138]  Tom Ellis,et al.  Designing efficient translation , 2018, Nature Biotechnology.

[139]  Ramon Diaz-Uriarte,et al.  Identifying restrictions in the order of accumulation of mutations during tumor progression: effects of passengers, evolutionary models, and sampling , 2015, BMC Bioinformatics.

[140]  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.

[141]  Lee Altenberg,et al.  Evolving better representations through selective genome growth , 1994, Proceedings of the First IEEE Conference on Evolutionary Computation. IEEE World Congress on Computational Intelligence.

[142]  Harry Eugene Stanley,et al.  Robustness of a Network of Networks , 2010, Physical review letters.

[143]  S. Gould The Structure of Evolutionary Theory , 2002 .

[144]  Lee Altenberg,et al.  Genome Growth and the Evolution of the Genotype-Phenotype Map , 1995, Evolution and Biocomputation.

[145]  Alec A K Nielsen,et al.  Genetic circuit characterization and debugging using RNA‐seq , 2017, Molecular systems biology.

[146]  P. Hogeweg,et al.  The origin of a primordial genome through spontaneous symmetry breaking , 2017, Nature Communications.

[147]  Ard A. Louis,et al.  The Arrival of the Frequent: How Bias in Genotype-Phenotype Maps Can Steer Populations to Local Optima , 2014, PloS one.

[148]  Eric S. Haag,et al.  The Same but Different: Worms Reveal the Pervasiveness of Developmental System Drift , 2014, PLoS genetics.

[149]  Peter Clote,et al.  Rnaifold: a Constraint Programming Algorithm for RNA inverse Folding and molecular Design , 2013, J. Bioinform. Comput. Biol..

[150]  Stephen P. Miller,et al.  The Biochemical Architecture of an Ancient Adaptive Landscape , 2005, Science.

[151]  Adi Livnat,et al.  A mixability theory for the role of sex in evolution , 2008, Proceedings of the National Academy of Sciences.

[152]  J. Maynard Smith Natural Selection and the Concept of a Protein Space , 1970 .

[153]  Jeffrey E. Barrick,et al.  Balancing Robustness and Evolvability , 2006, PLoS biology.

[154]  J. Krug,et al.  Exploring the Effect of Sex on Empirical Fitness Landscapes , 2009, The American Naturalist.

[155]  Santiago F. Elena,et al.  Evolutionary Constraints to Viroid Evolution , 2009, Viruses.

[156]  H. A. Orr,et al.  The evolutionary genetics of speciation. , 1998, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[157]  James Sharpe,et al.  A unified design space of synthetic stripe-forming networks , 2014, Nature Communications.

[158]  G. Achaz,et al.  MAGELLAN: a tool to explore small fitness landscapes , 2015, bioRxiv.

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

[160]  Michael Lachmann,et al.  Evolution of Genetic Potential , 2005, PLoS Comput. Biol..

[161]  A. Hughes The evolution of functionally novel proteins after gene duplication , 1994, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[162]  Karthik Raman,et al.  The evolvability of programmable hardware , 2010, Journal of The Royal Society Interface.

[163]  A. Wagner,et al.  Evolutionary Innovations and the Organization of Protein Functions in Genotype Space , 2010, PloS one.

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

[165]  M. Lumb Antibiotic Production , 2002 .

[166]  Sandip Paul,et al.  Accelerated gene evolution through replication–transcription conflicts , 2013, Nature.

[167]  Paulien Hogeweg,et al.  Eco-evolutionary dynamics, coding structure and the information threshold , 2010, BMC Evolutionary Biology.

[168]  S. Carpenter,et al.  Early-warning signals for critical transitions , 2009, Nature.

[169]  Richard A. Watson,et al.  PERSPECTIVE:SIGN EPISTASIS AND GENETIC CONSTRAINT ON EVOLUTIONARY TRAJECTORIES , 2005 .

[170]  Walter Fontana,et al.  Fast folding and comparison of RNA secondary structures , 1994 .

[171]  Aya Kojima,et al.  fRNAdb: a platform for mining/annotating functional RNA candidates from non-coding RNA sequences , 2006, Nucleic Acids Res..

[172]  Paulien Hogeweg,et al.  A Synergism between Adaptive Effects and Evolvability Drives Whole Genome Duplication to Fixation , 2014, PLoS Comput. Biol..

[173]  Arun K. Ramani,et al.  Comparative RNAi Screens in C. elegans and C. briggsae Reveal the Impact of Developmental System Drift on Gene Function , 2014, PLoS genetics.

[174]  D Penny,et al.  Mass Survival of Birds Across the Cretaceous- Tertiary Boundary: Molecular Evidence , 1997, Science.

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

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

[177]  Jeffrey E. Barrick,et al.  Arresting Evolution. , 2017, Trends in genetics : TIG.

[178]  Vitor B. Pinheiro,et al.  Darwin Assembly: fast, efficient, multi-site bespoke mutagenesis , 2017 .

[179]  S. Beck Multiplex DNA sequencing. , 1993, Methods in molecular biology.

[180]  R. Milkman Selection differentials and selection coefficients. , 1978, Genetics.

[181]  A. Lindenmayer Mathematical models for cellular interactions in development. II. Simple and branching filaments with two-sided inputs. , 1968, Journal of theoretical biology.

[182]  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.

[183]  Santiago F. Elena,et al.  Effect of Host Species on Topography of the Fitness Landscape for a Plant RNA Virus , 2016, Journal of Virology.

[184]  Jay Shendure,et al.  High-resolution analysis of DNA regulatory elements by synthetic saturation mutagenesis , 2009, Nature Biotechnology.

[185]  Axel Bender,et al.  Degeneracy: a design principle for achieving robustness and evolvability. , 2009, Journal of theoretical biology.

[186]  Jakub Otwinowski,et al.  Inferring fitness landscapes by regression produces biased estimates of epistasis , 2014, Proceedings of the National Academy of Sciences.

[187]  Victor Greiff,et al.  Large-scale network analysis reveals the sequence space architecture of antibody repertoires , 2019, Nature Communications.

[188]  Henry H. Heng,et al.  Chapter 5 – The Genomic Landscape of Cancers , 2017 .

[189]  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.

[190]  Niko Beerenwinkel,et al.  Quantifying cancer progression with conjunctive Bayesian networks , 2009, Bioinform..

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

[192]  Joshua L. Payne,et al.  The Robustness and Evolvability of Transcription Factor Binding Sites , 2014, Science.

[193]  B. Charlesworth,et al.  Genetic Revolutions, Founder Effects, and Speciation , 1984 .

[194]  Sebastian Bonhoeffer,et al.  How Good Are Statistical Models at Approximating Complex Fitness Landscapes? , 2016, Molecular biology and evolution.

[195]  S. Ahnert Structural properties of genotype–phenotype maps , 2017, Journal of The Royal Society Interface.

[196]  Bhavin S. Khatri,et al.  Statistical mechanics of convergent evolution in spatial patterning , 2009, Proceedings of the National Academy of Sciences.

[197]  Ekaterina V Putintseva,et al.  An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape , 2019, PLoS genetics.

[198]  F. Markowetz,et al.  Cancer Evolution: Mathematical Models and Computational Inference , 2014, Systematic biology.

[199]  Ting Hu,et al.  Evolutionary dynamics on multiple scales: a quantitative analysis of the interplay between genotype, phenotype, and fitness in linear genetic programming , 2012, Genetic Programming and Evolvable Machines.

[200]  Yann Ponty,et al.  Design of RNAs: comparing programs for inverse RNA folding , 2017, Briefings Bioinform..

[201]  Ard A Louis,et al.  Epistasis can lead to fragmented neutral spaces and contingency in evolution , 2011, Proceedings of the Royal Society B: Biological Sciences.

[202]  Dennis Claessen,et al.  Antibiotic production in Streptomyces is organized by a division of labour through terminal genomic differentiation , 2019, bioRxiv.

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

[204]  Robert B. Heckendorn,et al.  Should evolutionary geneticists worry about higher-order epistasis? , 2013, Current opinion in genetics & development.

[205]  Eric J Alm,et al.  Metagenomic mining of regulatory elements enables programmable species-selective gene expression , 2018, Nature Methods.

[206]  Andreas Wagner,et al.  A comparison of genotype-phenotype maps for RNA and proteins. , 2012, Biophysical journal.

[207]  Lei Dai,et al.  Generic Indicators for Loss of Resilience Before a Tipping Point Leading to Population Collapse , 2012, Science.

[208]  Joachim Krug,et al.  Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene , 2013, Molecular biology and evolution.

[209]  S. Gavrilets Evolution and speciation on holey adaptive landscapes. , 1997, Trends in ecology & evolution.

[210]  Y. Iwasa,et al.  Free fitness that always increases in evolution. , 1988, Journal of theoretical biology.

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

[212]  S. Nee,et al.  Phylogenetics and speciation. , 2001, Trends in ecology & evolution.

[213]  P. Hogeweg,et al.  Less Can Be More: RNA-Adapters May Enhance Coding Capacity of Replicators , 2012, PloS one.

[214]  M. Eigen,et al.  Viral quasispecies. , 1993, Scientific American.

[215]  Luis Mario Floría,et al.  Evolution of Cooperation in Multiplex Networks , 2012, Scientific Reports.

[216]  J. Coyne,et al.  INTRINSIC REPRODUCTIVE ISOLATION BETWEEN TWO SISTER SPECIES OF DROSOPHILA , 2009, Evolution; international journal of organic evolution.

[217]  Richard A. Goldstein,et al.  Population Size Dependence of Fitness Effect Distribution and Substitution Rate Probed by Biophysical Model of Protein Thermostability , 2013, Genome biology and evolution.

[218]  K. Young,et al.  THE ACCUMULATION OF REPRODUCTIVE INCOMPATIBILITIES IN AFRICAN CICHLID FISH , 2010, Evolution; international journal of organic evolution.

[219]  R. Lenski,et al.  Test of synergistic interactions among deleterious mutations in bacteria , 1997, Nature.

[220]  Arlin Stoltzfus,et al.  Mutational Biases Influence Parallel Adaptation , 2017, bioRxiv.

[221]  R. Lande Expected time for random genetic drift of a population between stable phenotypic states. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[222]  U. Alon,et al.  Spontaneous evolution of modularity and network motifs. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[223]  G. Wagner,et al.  Mutational robustness can facilitate adaptation , 2010, Nature.

[224]  Peter Clote,et al.  RNAiFold2T: Constraint Programming design of thermo-IRES switches , 2016, Bioinform..

[225]  Glen Liszczak,et al.  Nucleic Acid-Barcoding Technologies: Converting DNA Sequencing into a Broad-Spectrum Molecular Counter. , 2019, Angewandte Chemie.

[226]  J. Sabina,et al.  Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. , 1999, Journal of molecular biology.

[227]  Paulien Hogeweg,et al.  Spiral wave structure in pre-biotic evolution: hypercycles stable against parasites , 1991 .

[228]  Richard A. Goldstein,et al.  Evolutionary stochastic dynamics of speciation and a simple genotype-phenotype map for protein binding DNA , 2013, 1303.7006.

[229]  P. Schuster Prediction of RNA secondary structures: from theory to models and real molecules , 2006 .

[230]  Peter Jeavons,et al.  Model genotype–phenotype mappings and the algorithmic structure of evolution , 2019, Journal of the Royal Society Interface.

[231]  Javier M. Buldú,et al.  Competition among networks highlights the power of the weak , 2016, Nature Communications.

[232]  A. Wagner Robustness and evolvability: a paradox resolved , 2008, Proceedings of the Royal Society B: Biological Sciences.

[233]  M. Huynen,et al.  Smoothness within ruggedness: the role of neutrality in adaptation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[234]  J. True,et al.  Developmental system drift and flexibility in evolutionary trajectories , 2001, Evolution & development.

[235]  P. Alberch From genes to phenotype: dynamical systems and evolvability , 2004, Genetica.

[236]  Richard W. Lusk,et al.  Organismal complexity, protein complexity, and gene duplicability , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[237]  N. Barton,et al.  The frequency of shifts between alternative equilibria. , 1987, Journal of theoretical biology.

[238]  Howard Ochman,et al.  Gene location and bacterial sequence divergence. , 2002, Molecular biology and evolution.

[239]  Robert D. Finn,et al.  Rfam 13.0: shifting to a genome-centric resource for non-coding RNA families , 2017, Nucleic Acids Res..

[240]  Peter F. Stadler,et al.  ViennaRNA Package 2.0 , 2011, Algorithms for Molecular Biology.

[241]  V. Pande,et al.  On the application of statistical physics to evolutionary biology. , 2009, Journal of theoretical biology.

[242]  J. McCaskill The equilibrium partition function and base pair binding probabilities for RNA secondary structure , 1990, Biopolymers.

[243]  Susanna Manrubia,et al.  Evolution on neutral networks accelerates the ticking rate of the molecular clock , 2013, Journal of The Royal Society Interface.

[244]  T. O. Diener Potato spindle tuber "virus". IV. A replicating, low molecular weight RNA. , 1971, Virology.

[245]  C V Forst,et al.  Replication and mutation on neutral networks , 2001, Bulletin of mathematical biology.

[246]  Mark Newman,et al.  Networks: An Introduction , 2010 .

[247]  R. May Thresholds and breakpoints in ecosystems with a multiplicity of stable states , 1977, Nature.

[248]  F. Taddei,et al.  Evolution of Evolvability a , 1999 .

[249]  Devin Greene,et al.  The peaks and geometry of fitness landscapes. , 2013, Journal of theoretical biology.

[250]  Elhanan Borenstein,et al.  An End to Endless Forms: Epistasis, Phenotype Distribution Bias, and Nonuniform Evolution , 2008, PLoS Comput. Biol..

[251]  Harry Eugene Stanley,et al.  Catastrophic cascade of failures in interdependent networks , 2009, Nature.

[252]  Eugene I Shakhnovich,et al.  Structural determinant of protein designability. , 2002, Physical review letters.

[253]  Léon Bottou,et al.  Large-Scale Machine Learning with Stochastic Gradient Descent , 2010, COMPSTAT.

[254]  Eugene I. Shakhnovich,et al.  Protein stability imposes limits on organism complexity and speed of molecular evolution , 2007, Proceedings of the National Academy of Sciences.

[255]  A. F. Bennett,et al.  Experimental tests of the roles of adaptation, chance, and history in evolution. , 1995, Science.

[256]  M. Lässig,et al.  Evolutionary population genetics of promoters: predicting binding sites and functional phylogenies. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[257]  Paulien Hogeweg,et al.  Multilevel Selection in Models of Prebiotic Evolution II: A Direct Comparison of Compartmentalization and Spatial Self-Organization , 2009, PLoS Comput. Biol..

[258]  Nicolas E. Buchler,et al.  Effect of alphabet size and foldability requirements on protein structure designability , 1999, Proteins.

[259]  Michael Manhart,et al.  Protein folding and binding can emerge as evolutionary spandrels through structural coupling , 2014, Proceedings of the National Academy of Sciences.

[260]  Andreas Wagner,et al.  A latent capacity for evolutionary innovation through exaptation in metabolic systems , 2013, Nature.

[261]  Adam Paul Arkin,et al.  Evaluation of 244,000 synthetic sequences reveals design principles to optimize translation in Escherichia coli , 2018, Nature Biotechnology.

[262]  Peter F. Stadler,et al.  Genotype-Phenotype Maps , 2006 .

[263]  R. Lenski,et al.  Negative Epistasis Between Beneficial Mutations in an Evolving Bacterial Population , 2011, Science.

[264]  François Blanquart,et al.  Epistasis and the Structure of Fitness Landscapes: Are Experimental Fitness Landscapes Compatible with Fisher’s Geometric Model? , 2015, Genetics.

[265]  Thierry Mora,et al.  Physical epistatic landscape of antibody binding affinity , 2017, bioRxiv.

[266]  Ben Lehner,et al.  The Causes and Consequences of Genetic Interactions (Epistasis). , 2019, Annual review of genomics and human genetics.

[267]  T. Gorochowski,et al.  Absolute quantification of translational regulation and burden using combined sequencing approaches , 2018, bioRxiv.

[268]  Thomas Lenormand,et al.  Distributions of epistasis in microbes fit predictions from a fitness landscape model , 2007, Nature Genetics.

[269]  Steven A. Frank,et al.  Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer , 2012, PLoS biology.

[270]  Alexander Y. Tulchinsky,et al.  Hybrid Incompatibility Arises in a Sequence-Based Bioenergetic Model of Transcription Factor Binding , 2014, Genetics.

[271]  Sebastian Bonhoeffer,et al.  Exploring the Complexity of the HIV-1 Fitness Landscape , 2012, PLoS genetics.

[272]  R. Lande EFFECTIVE DEME SIZES DURING LONG‐TERM EVOLUTION ESTIMATED FROM RATES OF CHROMOSOMAL REARRANGEMENT , 1979, Evolution; international journal of organic evolution.

[273]  Eric L. Miller,et al.  The Ascent of the Abundant: How Mutational Networks Constrain Evolution , 2008, PLoS Comput. Biol..

[274]  Joshua L. Payne,et al.  RNA-mediated gene regulation is less evolvable than transcriptional regulation , 2018, Proceedings of the National Academy of Sciences.

[275]  E. Gerhart H. Wagner,et al.  Massive functional mapping of a 5′-UTR by saturation mutagenesis, phenotypic sorting and deep sequencing , 2013, Nucleic acids research.

[276]  Tom C B McLeish,et al.  Are there ergodic limits to evolution? Ergodic exploration of genome space and convergence , 2015, Interface Focus.

[277]  S. Ahnert,et al.  The organization of biological sequences into constrained and unconstrained parts determines fundamental properties of genotype–phenotype maps , 2015, Journal of The Royal Society Interface.

[278]  G A Petsko,et al.  Adjustment of conformational flexibility is a key event in the thermal adaptation of proteins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[279]  E. Borenstein,et al.  Direct evolution of genetic robustness in microRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[280]  G. Wagner,et al.  The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms , 2011, Nature Reviews Genetics.

[281]  Charles Ofria,et al.  Avida , 2004, Artificial Life.

[282]  W. Bateson,et al.  Darwin and Modern Science: Heredity and Variation in Modern Lights , 2009 .

[283]  Carl Troein,et al.  Enumerating Designing Sequences in the HP Model , 2002, Journal of biological physics.

[284]  P. Schuster,et al.  IR-98-039 / April Continuity in Evolution : On the Nature of Transitions , 1998 .

[285]  B. Ganem RNA world , 1987, Nature.

[286]  J. Plotkin,et al.  Inferring the shape of global epistasis , 2018, Proceedings of the National Academy of Sciences.

[287]  T. Metzinger The evolution of evolvability Ruth Garret Millikan Varieties of Meaning: The 2002 Jean Nicod Lectures , 2005, Trends in Cognitive Sciences.

[288]  N. Johnson,et al.  Toward a new synthesis: population genetics and evolutionary developmental biology. , 2001 .

[289]  Jennifer L. Knies,et al.  FISHER'S GEOMETRIC MODEL OF ADAPTATION MEETS THE FUNCTIONAL SYNTHESIS: DATA ON PAIRWISE EPISTASIS FOR FITNESS YIELDS INSIGHTS INTO THE SHAPE AND SIZE OF PHENOTYPE SPACE , 2013, Evolution; international journal of organic evolution.

[290]  Anton Crombach,et al.  Evolution of Evolvability in Gene Regulatory Networks , 2008, PLoS Comput. Biol..

[291]  Christian M. Reidys,et al.  Degeneracy and genetic assimilation in RNA evolution , 2018, BMC Bioinformatics.

[292]  S. Manrubia,et al.  Motif frequency and evolutionary search times in RNA populations. , 2011, Journal of theoretical biology.

[293]  B A Blount,et al.  Rapid host strain improvement by in vivo rearrangement of a synthetic yeast chromosome , 2018, Nature Communications.

[294]  Armita Nourmohammad,et al.  Evolution of molecular phenotypes under stabilizing selection , 2013, 1301.3981.

[295]  Johannes Berg,et al.  Adaptive evolution of transcription factor binding sites , 2003, BMC Evolutionary Biology.

[296]  Helen Yap Faculty of 1000 evaluation for Approaching a state shift in Earth's biosphere. , 2012 .

[297]  Stéphanie Bedhomme,et al.  Emerging viruses: why they are not jacks of all trades? , 2015, Current opinion in virology.

[298]  Jianzhi Zhang,et al.  The fitness landscape of a tRNA gene , 2016, Science.

[299]  Alexandre V. Morozov,et al.  Biophysical Fitness Landscapes for Transcription Factor Binding Sites , 2013, PLoS Comput. Biol..

[300]  Susanna Manrubia,et al.  Populations of genetic circuits are unable to find the fittest solution in a multilevel genotype-phenotype map , 2019, bioRxiv.

[301]  L. Altenberg Modularity in Evolution: Some Low-Level Questions ∗ , 2005 .

[302]  Craig R. Miller,et al.  Epistasis between Beneficial Mutations and the Phenotype-to-Fitness Map for a ssDNA Virus , 2011, PLoS genetics.

[303]  A. Lindenmayer Mathematical models for cellular interactions in development. I. Filaments with one-sided inputs. , 1968, Journal of theoretical biology.

[304]  Adi Livnat,et al.  Sex, mixability, and modularity , 2010, Proceedings of the National Academy of Sciences.

[305]  Santiago F. Elena,et al.  Efficient escape from local optima in a highly rugged fitness landscape by evolving RNA virus populations , 2016, Proceedings of the Royal Society B: Biological Sciences.

[306]  Paul Joyce,et al.  An empirical test of the mutational landscape model of adaptation using a single-stranded DNA virus , 2005, Nature Genetics.

[307]  Susanna Manrubia,et al.  Enumerating secondary structures and structural moieties for circular RNAs. , 2016, Journal of theoretical biology.

[308]  Julius Fredens,et al.  Total synthesis of Escherichia coli with a recoded genome , 2019, Nature.

[309]  Joachim Krug,et al.  Recombination and mutational robustness in neutral fitness landscapes , 2019, bioRxiv.

[310]  Thomas E Gorochowski,et al.  Using synthetic biological parts and microbioreactors to explore the protein expression characteristics of Escherichia coli. , 2014, ACS synthetic biology.

[311]  David W Hall,et al.  Fitness epistasis among 6 biosynthetic loci in the budding yeast Saccharomyces cerevisiae. , 2010, The Journal of heredity.

[312]  Santiago F. Elena,et al.  Virus Adaptation by Manipulation of Host's Gene Expression , 2008, PloS one.

[313]  P. Green,et al.  Transcription-associated mutational asymmetry in mammalian evolution , 2003, Nature Genetics.

[314]  A. E. Hirsh,et al.  The application of statistical physics to evolutionary biology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[315]  Carlos Espinosa-Soto,et al.  On the role of sparseness in the evolution of modularity in gene regulatory networks , 2018, PLoS Comput. Biol..

[316]  Qijun He,et al.  An Efficient Dual Sampling Algorithm with Hamming Distance Filtration , 2017, J. Comput. Biol..

[317]  Michael Zuker,et al.  Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information , 1981, Nucleic Acids Res..

[318]  M. Eigen,et al.  The Hypercycle , 2004, Naturwissenschaften.

[319]  M. Huynen Exploring phenotype space through neutral evolution , 1996, Journal of Molecular Evolution.

[320]  D. Mosier,et al.  Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region , 2010, Genetics.

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

[322]  Arlin Stoltzfus,et al.  Understanding Bias in the Introduction of Variation as an Evolutionary Cause , 2018, Evolutionary Causation.

[323]  Joshua L. Payne,et al.  The causes of evolvability and their evolution , 2018, Nature Reviews Genetics.

[324]  Mitsuyoshi Ueda,et al.  High-throughput evaluation of T7 promoter variants using biased randomization and DNA barcoding , 2018, PloS one.

[325]  J. Shendure,et al.  The power of multiplexed functional analysis of genetic variants , 2016, Nature Protocols.

[326]  Sebastian Bonhoeffer,et al.  A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase , 2011, Nature Genetics.

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

[328]  J. Krug,et al.  Empirical fitness landscapes and the predictability of evolution , 2014, Nature Reviews Genetics.

[329]  S. Tans,et al.  Breaking evolutionary constraint with a tradeoff ratchet , 2015, Proceedings of the National Academy of Sciences.

[330]  Claus O. Wilke,et al.  Adaptive evolution on neutral networks , 2001, Bulletin of mathematical biology.

[331]  Ard A Louis,et al.  Contingency, convergence and hyper-astronomical numbers in biological evolution. , 2016, Studies in history and philosophy of biological and biomedical sciences.

[332]  FRANK B. SALISBURY,et al.  Natural Selection and the Complexity of the Gene , 1969, Nature.

[333]  Thomas D. Cuypers,et al.  Evolution of evolvability and phenotypic plasticity in virtual cells , 2017, BMC Evolutionary Biology.

[334]  Charles Ofria,et al.  The genotype-phenotype map of an evolving digital organism , 2017, PLoS Comput. Biol..

[335]  Guido Sanguinetti,et al.  Network of epistatic interactions within a yeast snoRNA , 2016, Science.

[336]  Michael Levitt,et al.  Roles of mutation and recombination in the evolution of protein thermodynamics , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[337]  Dan S. Tawfik,et al.  The 'evolvability' of promiscuous protein functions , 2005, Nature Genetics.

[338]  Arnaud Martin,et al.  The differential view of genotype–phenotype relationships , 2015, Front. Genet..

[339]  P. Keightley,et al.  A Comparison of Models to Infer the Distribution of Fitness Effects of New Mutations , 2013, Genetics.

[340]  D. McShea,et al.  Biology's First Law: The Tendency for Diversity and Complexity to Increase in Evolutionary Systems , 2010 .

[341]  Thanat Chookajorn,et al.  Stepwise acquisition of pyrimethamine resistance in the malaria parasite , 2009, Proceedings of the National Academy of Sciences.

[342]  Douglas Densmore,et al.  Design Automation in Synthetic Biology. , 2017, Cold Spring Harbor perspectives in biology.

[343]  Paulien Hogeweg,et al.  Virtual Genomes in Flux: An Interplay of Neutrality and Adaptability Explains Genome Expansion and Streamlining , 2012, Genome biology and evolution.

[344]  Erle C. Ellis,et al.  Does the terrestrial biosphere have planetary tipping points? , 2013, Trends in ecology & evolution.

[345]  D. J. Kiviet,et al.  Empirical fitness landscapes reveal accessible evolutionary paths , 2007, Nature.

[346]  M. Ostermeier,et al.  Environmental changes bridge evolutionary valleys , 2016, Science Advances.

[347]  Niko Beerenwinkel,et al.  Computational Cancer Biology: An Evolutionary Perspective , 2016, PLoS Comput. Biol..

[348]  Susanna Manrubia,et al.  Distribution of genotype network sizes in sequence-to-structure genotype–phenotype maps , 2017, Journal of The Royal Society Interface.

[349]  Bas J Zwaan,et al.  Local Fitness Landscapes Predict Yeast Evolutionary Dynamics in Directionally Changing Environments , 2017, Genetics.

[350]  Elizabeth C. Theil,et al.  Epochal Evolution Shapes the Phylodynamics of Interpandemic Influenza A (H3N2) in Humans , 2006, Science.

[351]  S. Manrubia,et al.  Tipping points and early warning signals in the genomic composition of populations induced by environmental changes , 2015, Scientific Reports.

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

[353]  G. Oster,et al.  Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination. , 1979, Journal of theoretical biology.

[354]  Ben Lehner,et al.  Combinatorial Genetics Reveals a Scaling Law for the Effects of Mutations on Splicing , 2019, Cell.

[355]  Andreas Wagner,et al.  Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution , 2018, Molecular systems biology.

[356]  Andreas Wagner,et al.  Robustness Can Evolve Gradually in Complex Regulatory Gene Networks with Varying Topology , 2007, PLoS Comput. Biol..

[357]  L. Hurst,et al.  Faster Evolving Primate Genes Are More Likely to Duplicate , 2017, Molecular biology and evolution.

[358]  O. Tenaillon,et al.  The Utility of Fisher's Geometric Model in Evolutionary Genetics. , 2014, Annual review of ecology, evolution, and systematics.

[359]  Joshua B Edel,et al.  Single molecule multiplexed nanopore protein screening in human serum using aptamer modified DNA carriers , 2017, Nature Communications.

[360]  Javier M. Buldú,et al.  Successful strategies for competing networks , 2013, ArXiv.

[361]  Jacob G. Scott,et al.  The Damaging Effect of Passenger Mutations on Cancer Progression. , 2017, Cancer research.

[362]  Ramon Diaz-Uriarte,et al.  Every which way? On predicting tumor evolution using cancer progression models , 2018, bioRxiv.

[363]  A. Wagner How the global structure of protein interaction networks evolves , 2002, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[364]  Aaron W Feldman,et al.  A Semi-Synthetic Organism that Stores and Retrieves Increased Genetic Information , 2017, Nature.

[365]  S. Elena,et al.  The impact of high‐order epistasis in the within‐host fitness of a positive‐sense plant RNA virus , 2015, Journal of evolutionary biology.

[366]  P. Schuster,et al.  Statistics of RNA secondary structures , 1993, Biopolymers.

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

[368]  Sebastian E Ahnert,et al.  Evolutionary dynamics in a simple model of self-assembly. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[369]  Per Kristian Lehre,et al.  Phenotypic complexity and local variations in neutral degree , 2007, Biosyst..

[370]  Kristen K. Dang,et al.  Sexual reproduction selects for robustness and negative epistasis in artificial gene networks , 2006, Nature.

[371]  Parsimonious scenario for the emergence of viroid-like replicons de novo , 2019 .

[372]  Thomas E. Gorochowski,et al.  Registry in a tube: multiplexed pools of retrievable parts for genetic design space exploration , 2016, Nucleic acids research.

[373]  D. M. Taverna,et al.  Why are proteins marginally stable? , 2002, Proteins.

[374]  Rob Knight,et al.  Natural selection is not required to explain universal compositional patterns in rRNA secondary structure categories. , 2006, RNA.

[375]  Susanna Manrubia,et al.  toyLIFE: a computational framework to study the multi-level organisation of the genotype-phenotype map , 2014, Scientific Reports.

[376]  Joshua L. Payne,et al.  A thousand empirical adaptive landscapes and their navigability , 2017, Nature Ecology &Evolution.

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

[378]  Benjamin M. Fitzpatrick,et al.  RATES OF EVOLUTION OF HYBRID INVIABILITY IN BIRDS AND MAMMALS , 2004, Evolution; international journal of organic evolution.

[379]  Y. Pilpel,et al.  Chromosomal duplication is a transient evolutionary solution to stress , 2012, Proceedings of the National Academy of Sciences.

[380]  Robert D. Leclerc Survival of the sparsest: robust gene networks are parsimonious , 2008, Molecular systems biology.

[381]  Shawn M Gomez,et al.  Recombination drives the evolution of mutational robustness. , 2019, Current opinion in systems biology.

[382]  R. B. Azevedo,et al.  Emergent Speciation by Multiple Dobzhansky–Muller Incompatibilities , 2014, bioRxiv.

[383]  Anton Crombach,et al.  Quantitative system drift compensates for altered maternal inputs to the gap gene network of the scuttle fly Megaselia abdita , 2014, eLife.

[384]  Joachim Krug,et al.  Robustness and epistasis in mutation-selection models , 2009, Physical biology.

[385]  Yang I Li,et al.  An Expanded View of Complex Traits: From Polygenic to Omnigenic , 2017, Cell.

[386]  Luis Serrano,et al.  A reporter system coupled with high-throughput sequencing unveils key bacterial transcription and translation determinants , 2017, Nature Communications.

[387]  Susanna Manrubia,et al.  Adaptive multiscapes: an up-to-date metaphor to visualize molecular adaptation , 2017, Biology Direct.

[388]  S. K. Wyatt,et al.  Fitness valleys constrain HIV‐1's adaptation to its secondary chemokine coreceptor , 2014, Journal of evolutionary biology.