Comprehensive experimental fitness landscape and evolutionary network for small RNA

Significance Evolution by natural selection is driven by fitness differences, which define a “fitness landscape” in the space of all possible genetic sequences. Understanding the landscape is critical for understanding and predicting natural selection, yet very little is known about the structure of a real fitness landscape. Here we experimentally determine the complete fitness landscape of small RNA selected to interact with GTP, a building block for early life. We find that the landscape is composed of largely disconnected islands of active sequences. This scenario suggests that natural selection under these conditions would be constrained to local exploration of sequence space but that replaying the initial emergence of a functional RNA could lead to a different outcome. The origin of life is believed to have progressed through an RNA world, in which RNA acted as both genetic material and functional molecules. The structure of the evolutionary fitness landscape of RNA would determine natural selection for the first functional sequences. Fitness landscapes are the subject of much speculation, but their structure is essentially unknown. Here we describe a comprehensive map of a fitness landscape, exploring nearly all of sequence space, for short RNAs surviving selection in vitro. With the exception of a small evolutionary network, we find that fitness peaks are largely isolated from one another, highlighting the importance of historical contingency and indicating that natural selection would be constrained to local exploration in the RNA world.

[1]  Christopher L. Warren,et al.  Defining the sequence-recognition profile of DNA-binding molecules. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Pardi,et al.  Imino proton exchange rates imply an induced‐fit binding mechanism for the VEGF165‐targeting aptamer, Macugen , 2008, FEBS letters.

[3]  G. F. Joyce,et al.  Amplification, mutation and selection of catalytic RNA. , 1989, Gene.

[4]  G. F. Joyce,et al.  Self-Sustained Replication of an RNA Enzyme , 2009, Science.

[5]  J R Lorsch,et al.  Chance and necessity in the selection of nucleic acid catalysts. , 1996, Accounts of chemical research.

[6]  Peter F. Stadler,et al.  Landscapes: Complex Optimization Problems and Biopolymer Structures , 1994, Comput. Chem..

[7]  Vladimir I. Levenshtein,et al.  Binary codes capable of correcting deletions, insertions, and reversals , 1965 .

[8]  J. Gravner,et al.  Percolation on the fitness hypercube and the evolution of reproductive isolation. , 1997, Journal of theoretical biology.

[9]  C V Forst,et al.  Molecular evolution of catalysis. , 2000, Journal of theoretical biology.

[10]  R. Knight,et al.  Size, constant sequences, and optimal selection. , 2005, RNA.

[11]  I. Chou,et al.  RNA with iron(II) as a cofactor catalyses electron transfer. , 2013, Nature chemistry.

[12]  A genotype-to-phenotype map of in vitro selected RNA-cleaving DNAzymes: implications for accessing the target phenotype , 2009, Nucleic acids research.

[13]  Donald H. Burke,et al.  Evolutionary Landscapes for the Acquisition of New Ligand Recognition by RNA Aptamers , 2003, Journal of Molecular Evolution.

[14]  N. Lehman.  A Recombination‐Based Model for the Origin and Early Evolution of Genetic Information , 2008, Chemistry & biodiversity.

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

[16]  N. Barton.  Fitness Landscapes and the Origin of Species , 2004 .

[17]  M. Rendel.  Adaptive evolutionary walks require neutral intermediates in RNA fitness landscapes. , 2011, Theoretical population biology.

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

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

[20]  F. H. C. CRICK,et al.  Origin of the Genetic Code , 1967, Nature.

[21]  K. Weeks,et al.  Fluorogenic resolution of ligand binding by a nucleic acid aptamer. , 2003, Journal of the American Chemical Society.

[22]  J. Szostak,et al.  Isolation of high-affinity GTP aptamers from partially structured RNA libraries , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Chao,et al.  Evolution by small steps and rugged landscapes in the RNA virus phi6. , 1999, Genetics.

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

[25]  J. Szostak,et al.  Evolution of aptamers with a new specificity and new secondary structures from an ATP aptamer. , 2003, RNA.

[26]  Yingfu Li,et al.  Diverse Evolutionary Trajectories Characterize a Community of RNA-Cleaving Deoxyribozymes: A Case Study into the Population Dynamics of In Vitro Selection , 2005, Journal of Molecular Evolution.

[27]  H. A. Orr,et al.  The genetic theory of adaptation: a brief history , 2005, Nature Reviews Genetics.

[28]  C. Ross,et al.  Polyglutamine fibrillogenesis: The pathway unfolds , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Lee Aaron Newberg,et al.  The Gibbs Centroid Sampler , 2007, Nucleic Acids Res..

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

[31]  Zhengdong D. Zhang,et al.  Rapid in vivo exploration of a 5S rRNA neutral network. , 2009, Journal of microbiological methods.

[32]  Eric J. Hayden,et al.  Environmental change exposes beneficial epistatic interactions in a catalytic RNA , 2012, Proceedings of the Royal Society B: Biological Sciences.

[33]  X. Chen,et al.  Evolutionary origins and directed evolution of RNA. , 2009, The international journal of biochemistry & cell biology.

[34]  Michael Yarus,et al.  Multiple translational products from a five-nucleotide ribozyme , 2010, Proceedings of the National Academy of Sciences.

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

[36]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[37]  R. Breaker,et al.  Adenine riboswitches and gene activation by disruption of a transcription terminator , 2004, Nature Structural &Molecular Biology.

[38]  G. Fox,et al.  Experimental investigation of an RNA sequence space , 1993, Origins of life and evolution of the biosphere.

[39]  C. Woese,et al.  On the fundamental nature and evolution of the genetic code. , 1966, Cold Spring Harbor symposia on quantitative biology.

[40]  L. Gold,et al.  Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. , 1990, Science.

[41]  S. Wright,et al.  Evolution in Mendelian Populations. , 1931, Genetics.

[42]  L. Orgel,et al.  Prebiotic chemistry and the origin of the RNA world. , 2004, Critical reviews in biochemistry and molecular biology.

[43]  Stephan H. Bernhart,et al.  Strategies for measuring evolutionary conservation of RNA secondary structures , 2008, BMC Bioinformatics.

[44]  James M. Carothers,et al.  Informational Complexity and Functional Activity of RNA Structures , 2004, Journal of the American Chemical Society.

[45]  Peter F Stadler,et al.  Fast and reliable prediction of noncoding RNAs , 2005, Proc. Natl. Acad. Sci. USA.

[46]  S. Kauffman,et al.  Towards a general theory of adaptive walks on rugged landscapes. , 1987, Journal of theoretical biology.

[47]  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.

[48]  D. Bartel,et al.  Accessing rare activities from random RNA sequences: the importance of the length of molecules in the starting pool. , 1997, Chemistry & biology.

[49]  L. Orgel.  Evolution of the genetic apparatus. , 1968, Journal of molecular biology.

[50]  J. Szostak,et al.  Aptamers selected for higher-affinity binding are not more specific for the target ligand. , 2006, Journal of the American Chemical Society.

[51]  G. Fox,et al.  Equally Parsimonious Pathways Through an RNA Sequence Space Are Not Equally Likely , 1997, Journal of Molecular Evolution.

[52]  Irene A. Chen,et al.  Cascade of reduced speed and accuracy after errors in enzyme-free copying of nucleic acid sequences. , 2013, Journal of the American Chemical Society.

[53]  Peter Schuster,et al.  Mathematical modeling of evolution. Solved and open problems , 2011, Theory in Biosciences.

[54]  James M Carothers,et al.  Solution structure of an informationally complex high-affinity RNA aptamer to GTP. , 2006, RNA.

[55]  D. Bolon,et al.  Experimental illumination of a fitness landscape , 2011, Proceedings of the National Academy of Sciences.

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

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

[58]  Chiaolong Hsiao,et al.  RNA Folding and Catalysis Mediated by Iron (II) , 2012, PloS one.

[59]  Michael Stich,et al.  Phenotypic effect of mutations in evolving populations of RNA molecules , 2010, BMC Evolutionary Biology.