期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：4
DOI：10.1073/pnas.2107005119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
The evolutionary origin of RNA stem structures and the preservation of their base pairing under a spontaneous and random mutation process have puzzled theoretical evolutionary biologists. DNA replication–related template switching is a mutation mechanism that creates reverse-complement copies of sequence regions within a genome by replicating briefly along either the complementary or nascent DNA strand. Depending on the relative positions and context of the four switch points, this process may produce a reverse-complement repeat capable of forming the stem of a perfect DNA hairpin or fix the base pairing of an existing stem. Template switching is typically thought to trigger large structural changes, and its possible role in the origin and evolution of RNA genes has not been studied. Here, we show that the reconstructed ancestral histories of RNA genes contain mutation patterns consistent with the DNA replication–related template switching. In addition to multibase compensatory mutations, the mechanism can explain complex sequence changes, although mutations breaking the structure rarely get fixed in evolution. Our results suggest a solution for the long-standing dilemma of RNA gene evolution and demonstrate how template switching can both create perfect stems with a single mutation event and help maintaining the stem structure over time. Interestingly, template switching also provides an elegant explanation for the asymmetric base pair frequencies within RNA stems.
