Local neutral networks help maintain inaccurately replicating ribozymes

PLoS One. 2014 Oct 9;9(10):e109987. doi: 10.1371/journal.pone.0109987. eCollection 2014.

Abstract

The error threshold of replication limits the selectively maintainable genome size against recurrent deleterious mutations for most fitness landscapes. In the context of RNA replication a distinction between the genotypic and the phenotypic error threshold has been made; where the latter concerns the maintenance of secondary structure rather than sequence. RNA secondary structure is treated as a proxy for function. The phenotypic error threshold allows higher per digit mutation rates than its genotypic counterpart, and is known to increase with the frequency of neutral mutations in sequence space. Here we show that the degree of neutrality, i.e. the frequency of nearest-neighbour (one-step) neutral mutants is a remarkably accurate proxy for the overall frequency of such mutants in an experimentally verifiable formula for the phenotypic error threshold; this we achieve by the full numerical solution for the concentration of all sequences in mutation-selection balance up to length 16. We reinforce our previous result that currently known ribozymes could be selectively maintained by the accuracy known from the best available polymerase ribozymes. Furthermore, we show that in silico stabilizing selection can increase the mutational robustness of ribozymes due to the fact that they were produced by artificial directional selection in the first place. Our finding offers a better understanding of the error threshold and provides further insight into the plausibility of an ancient RNA world.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Genetic Drift
  • Genetic Fitness
  • Models, Theoretical
  • Mutation
  • Nucleic Acid Conformation*
  • RNA / biosynthesis
  • RNA / genetics*
  • RNA, Catalytic / biosynthesis
  • RNA, Catalytic / genetics*
  • Selection, Genetic / genetics*
  • Sequence Analysis, RNA

Substances

  • RNA, Catalytic
  • RNA

Grants and funding

Financial support has been provided by the European Research Council under the European Community's Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no [294332] and the Hungarian National Office for Research and Technology (NAP 2005/KCKHA005). AS and ÁK acknowledge support by the European Union and co-financed by the European Social Fund (grant agreement no. TAMOP 4.2.1/B-09/1/KMR-2010-0003). This work was carried out as part of EU COST action CM1304 “Emergence and Evolution of Complex Chemical Systems”. ÁK gratefully acknowledges a János Bolyai Research Fellowship of the Hungarian Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.