ArticleJournal of the American Chemical Society2019
Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed.
- Coevolution of RNase P and the ribosome.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Using structured libraries, selection, and machine learning to rapidly explore the sequence space of a fluorescent deoxyribozyme.Nucleic acids research · 2025Article
- Article
- Exploring the space of self-reproducing ribozymes using generative models.Nature communications · 2025Article
- Article
- Assembly of catalytic complexes from randomized oligonucleotides.Science advances · 2025Article
- Rapid discovery of functional RNA domains.Nucleic acids research · 2025Article
- Principles ofJournal of the Royal Society, Interface · 2025Article
- Tailoring industrial enzymes for thermostability and activity evolution by the machine learning-based iCASE strategy.Nature communications · 2025Article
- Intellectual frameworks to understand complex biochemical systems at the origin of life.Nature chemistry · 2025Article
- Bioengineering hybrid artificial life.Frontiers in bioinformatics · 2025Review
- Optimized periphery-core interface increases fitness of the Bacillus subtilis glmS ribozyme.Nucleic acids research · 2024Article
- Evolution of the substrate specificity of an RNA ligase ribozyme from phosphorimidazole to triphosphate activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Prebiotic chiral transfer from self-aminoacylating ribozymes may favor either handedness.Nature communications · 2024Article
- A potential role for RNA aminoacylation prior to its role in peptide synthesis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Protocell Effects on RNA Folding, Function, and Evolution.Accounts of chemical research · 2024Article
- An anticodon-sensing T-boxzyme generates the elongator nonproteinogenic aminoacyl-tRNA in situ of a custom-made translation system for incorporation.Nucleic acids research · 2024Article
- Exploring the Landscape of Aptamers: From Cross-Reactive to Selective to Specific, High-Affinity Receptors for Cocaine.JACS Au · 2024Article
- Discovering pathways through ribozyme fitness landscapes using information theoretic quantification of epistasis.RNA (New York, N.Y.) · 2023Article
- Minimizing amplification bias during reverse transcription for in vitro selections.RNA (New York, N.Y.) · 2023Article
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8 authors.
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Abstract
Molecular evolution can be conceptualized as a walk over a "fitness landscape", or the function of fitness (e.g., catalytic activity) over the space of all possible sequences. Understanding evolution requires knowing the structure of the fitness landscape and identifying the viable evolutionary pathways through the landscape. However, the fitness landscape for any catalytic biomolecule is largely unknown. The evolution of catalytic RNA is of special interest because RNA is believed to have been foundational to early life. In particular, an essential activity leading to the genetic code would be the reaction of ribozymes with activated amino acids, such as 5(4 H)-oxazolones, to form aminoacyl-RNA. Here we combine in vitro selection with a massively parallel kinetic assay to map a fitness landscape for self-aminoacylating RNA, with nearly complete coverage of sequence space in a central 21-nucleotide region. The method (SCAPE: sequencing to measure catalytic activity paired with in vitro evolution) shows that the landscape contains three major ribozyme families (landscape peaks). An analysis of evolutionary pathways shows that, while local optimization within a ribozyme family would be possible, optimization of activity over the entire landscape would be frustrated by large valleys of low activity. The sequence motifs associated with each peak represent different solutions to the problem of catalysis, so the inability to traverse the landscape globally corresponds to an inability to restructure the ribozyme without losing activity. The frustrated nature of the evolutionary network suggests that chance emergence of a ribozyme motif would be more important than optimization by natural selection.
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