Natural and artificial RNAs occupy the same restricted region of sequence space
Open accessAbstract
Different chemical and mutational processes within genomes give rise to sequences with different compositions and perhaps different capacities for evolution. The evolution of functional RNAs may occur on a “neutral network” in which sequences with any given function can easily mutate to sequences with any other. This neutral network hypothesis is more likely if there is a particular region of composition that contains sequences that are functional in general, and if many different functions are possible within this preferred region of composition. We show that sequence preferences in active sites recovered by in vitro selection combine with biophysical folding rules to support the neutral network hypothesis. These simple active-site specifications and folding preferences obtained by artificial selection experiments recapture the previously observed purine bias and specific spread along the GC axis of naturally occurring aptamers and ribozymes isolated from organisms, although other types of RNAs, such as miRNA precursors and spliceosomal RNAs, that act primarily through complementarity to other amino acids do not share these preferences. These universal evolved sequence features are therefore intrinsic in RNA molecules that bind small-molecule targets or catalyze reactions.
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The effect of base composition on folding energy can be deduced from nearest-neighbor models of RNA folding.
“The effect of base composition on folding energy can be deduced from nearest-neighbor models of RNA folding (Kennedy et al. 2010; Lorenz et al. 2011; Derr et al. 2012)”
From The paradox of dual roles in the RNA world: resolving the conflict between stable folding and templating ability (2013) · cites this paper as Kennedy et al. 2010
Most aptamers and ribozymes have roughly even composition, with 22-28% of each nucleotide.
“Since most aptamers and ribozymes have roughly even composition [22–28% of each nucleotide; (29,30)]”
From The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA (2011) · cites this paper as [29]
Ribozymes and aptamers have relatively even composition compared to other RNAs.
“and indeed ribozymes and aptamers have relatively even composition compared to other RNAs (29).”
From The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA (2011) · cites this paper as [29]
A DNA genome might have tended toward a more even nucleotide composition.
“Therefore, a DNA genome might have tended toward a more even nucleotide composition, which could be advantageous since heavily GC-rich sequences pose practical problems (e.g. difficult strand separation), and indeed ribozymes and aptamers have relatively even composition compared to other RNAs (29).”
From The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA (2011) · cites this paper as [29]
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Cites
Tuerk, C., & Gold, L. (1990) · Science · doi:10.1126/science.2200121 · Cited by 10,421 · see citing works
In vitro selection of RNA molecules that bind specific ligands
Ellington, A. D., & Szostak, J. W. (1990) · Nature · doi:10.1038/346818a0 · Cited by 9,845 · see citing works
Probability: Theory and Examples.
Prewitt, K., & Durrett, R. T. (1992) · Journal of the American Statistical Association · doi:10.2307/2290301 · Cited by 3,238 · see citing works
Gilbert, W. (1986) · Nature · doi:10.1038/319618a0 · Cited by 2,721 · see citing works
Fast folding and comparison of RNA secondary structures
Hofacker, I. L., Fontana, W., Stadler, P. F., Bonhoeffer, S., Tacker, M., & Schuster, P. M. (1994) · Monatshefte für Chemie - Chemical Monthly · doi:10.1007/bf00818163 · Cited by 2,314 · see citing works
The Hypercycle: A principle of natural self-organization
Eigen, M., & Schuster, P. M. (1979) · Cited by 1,906 · see citing works
A principle of natural self-organization: Part A: Emergence of the hypercycle
Eigen, M., & Schuster, P. (1977) · Naturwissenschaften · doi:10.1007/bf00450633 · Cited by 1,752 · see citing works
Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA
Robertson, D. L., & Joyce, G. F. (1990) · Nature · doi:10.1038/344467a0 · Cited by 1,331 · see citing works
Directional mutation pressure and neutral molecular evolution.
Sueoka, N. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.8.2653 · Cited by 978 · see citing works
Rfam: updates to the RNA families database
Gardner, P. P., Daub, J., Tate, J. G., Nawrocki, E. P., Kolbe, D. L., Lindgreen, S., Wilkinson, A. C., Finn, R. D., Griffiths‐Jones, S., Eddy, S. R., et al. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn766 · Cited by 923 · see citing works
Improved predictions of secondary structures for RNA.
Jaeger, J. A., Turner, D. H., & Zuker, M. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.20.7706 · Cited by 817 · see citing works
RNA-catalyzed RNA polymerization: Accurate and general RNA-templated primer extension.
Johnston, W. K., Unrau, P. J., Lawrence, M. S., Glasner, M. E., & Bartel, D. P. (2001) · Science · doi:10.1126/science.1060786 · Cited by 768 · see citing works
ON THE GENETIC BASIS OF VARIATION AND HETEROGENEITY OF DNA BASE COMPOSITION
Sueoka, N. (1962) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.48.4.582 · Cited by 521 · see citing works
Continuity in evolution: on the nature of transitions.
Fontana, W., & Schuster, P. (1998) · Science · doi:10.1126/science.280.5368.1451 · Cited by 456 · see citing works
One sequence, two ribozymes: implications for the emergence of new ribozyme folds
Schultes, E. A., & Bartel, D. P. (2000) · Science · doi:10.1126/science.289.5478.448 · Cited by 364 · see citing works
Famulok, M. (1994) · Journal of the American Chemical Society · doi:10.1021/ja00084a010 · Cited by 287 · see citing works
Evolution in vitro of an RNA enzyme with altered metal dependence
Lehman, N., & Joyce, G. F. (1993) · Nature · doi:10.1038/361182a0 · Cited by 195 · see citing works
PyCogent: a toolkit for making sense from sequence
Knight, R. D., Maxwell, P., Birmingham, A., Carnes, J., Caporaso, J. G., Easton, B. C., Eaton, M., Hamady, M., Lindsay, H. A., Liu, Z. Z., et al. (2007) · Genome biology · doi:10.1186/gb-2007-8-8-r171 · Cited by 195 · see citing works
Self-citationIn vitro evolution suggests multiple origins for the hammerhead ribozyme
Salehi-Ashtiani, K., & Szostak, J. W. (2001) · Nature · doi:10.1038/35102081 · Cited by 183 · see citing works
Isolation of high-affinity GTP aptamers from partially structured RNA libraries
Davis, J. H., & Szostak, J. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182095699 · Cited by 179 · see citing works
A Small Aptamer with Strong and Specific Recognition of the Triphosphate of ATP
Sazani, P., Larralde, R., & Szostak, J. W. (2004) · Journal of the American Chemical Society · doi:10.1021/ja049171k · Cited by 159 · see citing works
Eigen, M., & Schuster, P. (1979) · Springer eBooks · doi:10.1007/978-3-642-67247-7_1 · Cited by 135 · see citing works
A story: unpaired adenosine bases in ribosomal RNAs
Gutell, R. R., Cannone, J. J., Shang, Z., Du, Y., & Serra, M. J. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4172 · Cited by 119 · see citing works
Lao, P. J., & Forsdyke, D. R. (2000) · Genome Research · doi:10.1101/gr.10.2.228 · Cited by 116 · see citing works
Evidence of common regularities in the composition of pentose nucleic acids
Elson, D., & Chargaff, E. (1955) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(55)90385-1 · Cited by 111 · see citing works
Smit, S., Yarus, M., & Knight, R. (2005) · RNA · doi:10.1261/rna.2183806 · Cited by 105 · see citing works
Self-citationA ribozyme composed of only two different nucleotides
Reader, J. S., & Joyce, G. F. (2002) · Nature · doi:10.1038/nature01185 · Cited by 100 · see citing works
Estimating the Contributions of Selection and Self-Organization in RNA Secondary Structure
Schultes, E., Hraber, P., & LaBean, T. H. (1999) · Journal of Molecular Evolution · doi:10.1007/pl00006536 · Cited by 96 · see citing works
A ribozyme that lacks cytidine
Rogers, J., & Joyce, G. F. (1999) · Nature · doi:10.1038/46335 · Cited by 94 · see citing works
Evolution of aptamers with a new specificity and new secondary structures from an ATP aptamer
Huang, Z., & Szostak, J. W. (2003) · RNA · doi:10.1261/rna.5990203 · Cited by 87 · see citing works
RNA Affinity for Molecular L-Histidine; Genetic Code Origins
Majerfeld, I. H., Puthenvedu, D., & Yarus, M. (2005) · Journal of Molecular Evolution · doi:10.1007/s00239-004-0360-9 · Cited by 68 · see citing works
Self-citationAbundance of correctly folded RNA motifs in sequence space, calculated on computational grids
Knight, R. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki886 · Cited by 63 · see citing works
Self-citationA diminutive and specific RNA binding site for L-tryptophan
Majerfeld, I. H. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki861 · Cited by 59 · see citing works
A computational proposal for designing structured RNA pools for in vitro selection of RNAs
Kim, N., Gan, H. H., & Tamar Schlick, A. (2007) · RNA · doi:10.1261/rna.374907 · Cited by 53 · see citing works
The distribution of RNA motifs in natural sequences
Bourdeau, V., Ferbeyre, G., Pageau, M., Paquin, B., & Cedergren, R. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.22.4457 · Cited by 47 · see citing works
Essential structures of a self-aminoacylating RNA
Illangasekare, M., Kovalchuke, O., & Yarus, M. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1414 · Cited by 41 · see citing works
Self-citationEvolutionary landscapes for the acquisition of new ligand recognition by RNA aptamers
Held, D. M., Travis Greathouse, S., Agrawal, A., & Burke, D. H. (2003) · Journal of Molecular Evolution · doi:10.1007/s00239-003-2481-y · Cited by 41 · see citing works
A More Complex Isoleucine Aptamer with a Cognate Triplet
Łęgiewicz, M., & Yarus, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502329200 · Cited by 38 · see citing works
Self-citationSchultes, E., Hraber, P., & LaBean, T. H. (1997) · PubMed · Cited by 37 · see citing works
Multiple pattern matching: a Markov chain approach
Lladser, M. E., Betterton, M. D., & Knight, R. D. (2007) · Journal of Mathematical Biology · doi:10.1007/s00285-007-0109-3 · Cited by 37 · see citing works
Self-citationRoquain, É., & Schbath, S. (2007) · Advances in Applied Probability · doi:10.1239/aap/1175266472 · Cited by 31 · see citing works
Predicting candidate genomic sequences that correspond to synthetic functional RNA motifs
Laserson, U. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki911 · Cited by 25 · see citing works
Substrate specificity and reaction kinetics of an X-motif ribozyme
Lazarev, D. S., Puskarz, I., & Breaker, R. R. (2003) · RNA · doi:10.1261/rna.2600503 · Cited by 19 · see citing works
Information, probability, and the abundance of the simplest RNA active sites
Kennedy, R. (2008) · Frontiers in bioscience · doi:10.2741/3137 · Cited by 12 · see citing works
Self-citationDatabase‐Driven Grid Computing and Distributed Web Applications: A Comparison
Sterck, H. D., Papo, A., Zhang, C., Hamady, M., & Knight, R. D. (2007) · doi:10.1002/9780470191637.ch11 · Cited by 2 · see citing works
Self-citationDatabase-Driven Grid Computing with GridBASE
Sterck, H. D., Zhang, C., & Papo, A. (2007) · International Conference on Advanced Information Networking and Applications Workshops (WAINA) · doi:10.1109/ainaw.2007.141 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Computational approaches to RNA structure prediction, analysis, and design
Laing, C., & Tamar Schlick, A. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.03.015 · Cited by 149 · see citing works
The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA
Leu, K., Obermayer, B., Rajamani, S., Gerland, U., & Chen, I. A. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr525 · Cited by 85 · see citing works
Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences
Derr, J., Manapat, M. L., Rajamani, S., Leu, K., Xulvi-Brunet, R., Joseph, I., Nowak, M. A., & Chen, I. A. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks065 · Cited by 74 · see citing works
The virtual circular genome model for primordial RNA replication
Zhou, L., Ding, D., & Szostak, J. W. (2020) · RNA · doi:10.1261/rna.077693.120 · Cited by 63 · see citing works
Ivica, N. A., Obermayer, B., Campbell, G. W., Rajamani, S., Gerland, U., & Chen, I. A. (2013) · Journal of Molecular Evolution · doi:10.1007/s00239-013-9584-x · Cited by 42 · see citing works
Type-II tRNAs and Evolution of Translation Systems and the Genetic Code
Kim, Y., Kowiatek, B. K., Opron, K., & Burton, Z. F. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103275 · Cited by 27 · see citing works
Protein Folding Absent Selection
LaBean, T. H., Butt, T. R., Kauffman, S. A., & Schultes, E. (2011) · Genes · doi:10.3390/genes2030608 · Cited by 27 · see citing works
Template-Free Assembly of Functional RNAs by Loop-Closing Ligation
Wu, L.-F., Liu, Z., Roberts, S. J., Su, M., Szostak, J. W., & Sutherland, J. D. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c05601 · Cited by 21 · see citing works
Motif frequency and evolutionary search times in RNA populations
Stich, M., & Manrubia, S. C. (2011) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2011.03.010 · Cited by 17 · see citing works
Nucleotides that are essential but not conserved; a sufficient L-tryptophan site in RNA
Majerfeld, I. H., Chocholoušová, J. V., Malaiya, V., Widmann, J. J., McDonald, D. T., Reeder, J., Iyer, M. K., Illangasekare, M., Yarus, M., & Knight, R. D. (2010) · RNA · doi:10.1261/rna.2220210 · Cited by 12 · see citing works
Self-citationOccupancy distributions in Markov chains via Doeblin's ergodicity coefficient
Chestnut, S. R., & Lladser, M. E. (2010) · Discrete Mathematics & Theoretical Computer Science · doi:10.46298/dmtcs.2789 · Cited by 9 · see citing works
Self-citationMallatt, J. M., & Chittenden, K. D. (2014) · Molecular Phylogenetics and Evolution · doi:10.1016/j.ympev.2013.12.007 · Cited by 8 · see citing works
Exponentially Few RNA Structures are Designable
Yao, H.-T., Régnier, M., Chauve, C., & Ponty, Y. (2019) · ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics (ACM-BCB) · doi:10.1145/3307339.3342163 · Cited by 7 · see citing works
RNA regulators responding to ribosomal protein S15 are frequent in sequence space
Slinger, B. L., & Meyer, M. M. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw754 · Cited by 7 · see citing works
On the emergence of structural complexity in RNA replicators
Oliver, C., Reinharz, V., & Waldispühl, J. (2019) · RNA · doi:10.1261/rna.070391.119 · Cited by 5 · see citing works
Replication elongates short DNA, reduces sequence bias and develops trimer structure
Serrão, A. C., Dänekamp, F., Meggyesi, Z., & Braun, D. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad1190 · Cited by 5 · see citing works
Kluwe, C., & Ellington, A. D. (2010) · Science · doi:10.1126/science.1197667 · Cited by 5 · see citing works
Perrin, D. M. (2012) · Elsevier eBooks · doi:10.1016/b978-0-444-53349-4.00220-x · Cited by 3 · see citing works
How Binding Affinity and Binding Specificity Map to Sequence Space
Liberles, D. A., & Meyer, M. M. (2026) · Journal of Molecular Evolution · doi:10.1007/s00239-026-10308-5 · Cited by 1 · see citing works
- Authors
- Kennedy, R., Lladser, M. E., Wu, Z., Zhang, C., Yarus, M., De Sterck, H., & Knight, R.
- Affiliations
- University of Colorado Boulder (US)
- University of Waterloo (CA)
- Howard Hughes Medical Institute (US)
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-12-23
- Volume
- 16
- Issue
- 2
- Pages
- 280-289
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC2811657
- OpenAlex
- W2149744450
- Cited by
- 19
- References
- 46
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2016: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- RNA (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Science Foundation (0805950)
- National Institutes of Health
- National Institute of General Medical Sciences (R01 GM48080, R01GM048080)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Keywords
- neutral networks, RNA evolution, in vitro selection, aptamers, ribozymes, GC content, RNA folding, sequence composition, microRNA precursors, small molecule binding
- MeSH terms
- Base Composition, Base Sequence, Binding Sites, Models, Genetic, Models, Molecular, Mutation, Nucleic Acid Conformation, RNA, Selection, Genetic, Models, Statistical, Poisson Distribution, RNA, Catalytic, Computational Biology, SELEX Aptamer Technique, Aptamers, Nucleotide, Biophysical Phenomena
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