Cooperative Ligation Breaks Sequence Symmetry and Stabilizes Early Molecular Replication
Each living species carries a complex DNA sequence that determines their unique features andfunctionalities. It is generally assumed that life started from a random pool of oligonucleotide sequences,generated by a prebiotic polymerization of nucleotides. The mechanism that initially facilitated theemergence of sequences that code for the function of the first species from such a random pool of sequencesremains unknown. It is a central problem of the origin of life. An interesting option would be a self-selection mechanism by spontaneous symmetry breaking. Initial concentration fluctuations of specificsequence motifs would have been amplified and outcompeted less abundant sequences, enhancing thesignal to noise to replicate and select functional sequences. Here, we demonstrate with experimental andtheoretical findings that templated ligation would provide such a self-selection. In templated ligation, twoadjacent single sequences strands are chemically joined when a third complementary strand sequencebrings them in close proximity. This simple mechanism is a likely side product of a prebioticpolymerization chemistry once the strands reach the length to form double-stranded species. As shownhere, the ligation gives rise to a nonlinear replication process by the cooperative ligation of matchingsequences which self-promote their own elongation. This process leads to a cascade of enhanced templatebinding and faster ligation reactions. A requirement is the reshuffling of the strands by thermal cycling,enabled, for example, by microscale convection. By using a limited initial sequence space and performinglong-term ligations, we find that complementary sequences with an initially higher concentration prevailover either noncomplementary or less-concentrated sequences. The latter die out by the moleculardegradation that we simulate in the experiment by serial dilution. The experimental results are consistentwith both explicit and abstract theory models that are generated considering the ligation rates determinedexperimentally. Previously, other nonlinear modes of replication such as hypercycles have been discussedto overcome instabilities from first-order replication dynamics such as the error catastrophe and thedominance of structurally simple but fast-replicating sequences, known as the Spiegelman problem.Assuming that templated ligation is driven by the same chemical mechanism that generates prebioticpolymerization of oligonucleotides, the mechanism could function as a missing link between polymeri-zation and the self-stabilized replication, offering a pathway to the autonomous emergence of Darwinianevolution for the origin of life.