Abstract
Significance RNA hairpin structures require perfect pairing between consecutive bases of the opposite sides of the stem. Random mutations are unlikely to create complex structures, so the origin of long stems and the maintenance of their perfect base pairing through compensatory substitutions have puzzled evolutionary biologists. We reconstructed ancestral sequence histories of RNA sequences and found mutation patterns consistent with template switching in DNA replication. We propose the template switch mutation mechanism as the explanation for the evolution of perfect stem structures and show that the mechanism also provides an elegant explanation for multinucleotide jumps in the sequence space and for the observed asymmetry in the stem base pair frequencies.
Highlights
Template switch mutation | hairpin loop | compensatory mutation | RNA secondary structure | ancestral sequence reconstruction studied in microbes [7, 8, 10, 11] and been aware of in eukaryotic research [12,13,14], but few studies have looked at the role of the resulting mutations in genes
We showed earlier that DNA replication–related template switch mutations (TSMs) [7, 8] can produce reverse-complement repeats needed for perfect DNA hairpins and fix the base pairing of existing stems [9]
We found similar TSMlike patterns creating novel stems within ribosomal RNA (rRNA) genes (Fig. 2 E and F)
Summary
Template switch mutation | hairpin loop | compensatory mutation | RNA secondary structure | ancestral sequence reconstruction studied in microbes [7, 8, 10, 11] and been aware of in eukaryotic research [12,13,14], but few studies have looked at the role of the resulting mutations in genes ( see ref. 15). We identified de novo hairpins and analyzed CMs consistent with the “two-step process” [3] In the latter, the intermediate state is observed such that the initial mutation breaking the base pairing is placed in one tree branch and the compensatory change is in another branch (Fig. 1A). Computational methods for inference and validation of RNA secondary structures exploit this [4, 5], and correlated base changes turning one Watson–Crick pair to another (e.g., A–U → G–C) are considered the ultimate evidence of a functionally important stem Such compensatory mutations (CMs) are commonly believed to happen via an intermediate state involving G–U base pairing [5]. We propose the template switch mutation mechanism as the explanation for the evolution of perfect stem structures and show that the mechanism provides an elegant explanation for multinucleotide jumps in the sequence space and for the observed asymmetry in the stem base pair frequencies
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