Effect of Stalling after Mismatches on the Error Catastrophe in Nonenzymatic Nucleic Acid Replication

Abstract

The frequency of errors during genome replication limits the amount of functionally important information that can be passed on from generation to generation. During the origin of life, mutation rates are thought to have been quite high, raising a classic chicken-and-egg paradox: could nonenzymatic replication propagate sequences accurately enough to allow for the emergence of heritable function? Here we show that the theoretical limit on genomic information content may increase substantially as a consequence of dramatically slowed polymerization after mismatches. As a result of postmismatch stalling, accurate copies of a template tend to be completed more rapidly than mutant copies and the accurate copies can therefore begin a second round of replication more quickly. To quantify this effect, we characterized an experimental model of nonenzymatic, template-directed nucleic acid polymerization. We found that most mismatches decrease the rate of primer extension by more than 2 orders of magnitude relative to a matched (Watson−Crick) control. A chemical replication system with this property would be able to propagate sequences long enough to have function. Our study suggests that the emergence of functional sequences during the origin of life would be possible even in the face of the high intrinsic error rates of chemical replication.

Motif frequency and evolutionary search times in RNA populations

“…It turns out that common structures are not only easier to find, but also withstand higher mutation rates and are therefore more evolvable. Although our simulations were not aimed to explain any specific scenario, the molecule length used here (n = 35) leads to critical error rates which are compatible with a recent experimental study for nonenzymatic nucleic acid replication (Rajamani et al, 2010).…”

The eightfold path to non-enzymatic RNA replication

“…Primer-extension following a mismatch can be much slower than following a Watson-Crick base-pair. Such post-mismatch stalling was originally noticed in enzymatic reactions [31,32] but is also significant in a non-enzymatic DNA template-copying model system [33]. The beneficial effect of post-mismatch stalling on fidelity is a consequence of the fact that those templates that are completed first tend to be the most accurately copied.…”

Synthesis of information-carrying polymers of mixed sequences from double stranded short deoxynucleotides

“…3'-amino-2', 3'-dideoxynucleotides have been used as model systems by the groups of Orgel [18], Richert [25] and Szostak [26]. After analyzing Orgel's work, we concluded that nontemplated cyclization of the single strands can be reduced if the rate of ligation to elongate the double strands is enhanced.…”