The error threshold for replication, the critical copying fidelity below which the fittest genotype deterministically disappears, limits the length of the genome that can be maintained by selection. Primordial replication must have been error-prone, and so early replicators are thought to have been necessarily short1. The error threshold also depends on the fitness landscape. In an RNA world2, many neutral and compensatory mutations can raise the threshold, below which the functional phenotype3, rather than a particular sequence, is still present4,5. Here we show, on the basis of comparative analysis of two extensively mutagenized ribozymes, that with a copying fidelity of 0.999 per digit per replication the phenotypic error threshold rises well above 7,000 nucleotides, which permits the selective maintenance of a functionally rich riboorganism6 with a genome of more than 100 different genes, the size of a tRNA. This requires an order of magnitude of improvement in the accuracy of in vitro-generated polymerase ribozymes7,8. Incidentally, this genome size coincides with that estimated for a minimal cell achieved by top-down analysis9, omitting the genes dealing with translation.
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