Abstract
DNA polymerase template switching between short, non-identical inverted repeats (IRs) is a genetic mechanism that leads to the homogenization of IR arms and to IR spacer inversion, which cause multinucleotide mutations (MNMs). It is unknown if and how template switching affects gene evolution. In this study, we performed a phylogenetic analysis to determine the effect of template switching between IR arms on coding DNA of Saccharomyces cerevisiae. To achieve this, perfect IRs that co-occurred with MNMs between a strain and its parental node were identified in S. cerevisiae strains. We determined that template switching introduced MNMs into 39 protein-coding genes through S. cerevisiae evolution, resulting in both arm homogenization and inversion of the IR spacer. These events in turn resulted in nonsynonymous substitutions and up to five neighboring amino acid replacements in a single gene. The study demonstrates that template switching is a powerful generator of multiple substitutions within codons. Additionally, some template switching events occurred more than once during S. cerevisiae evolution. Our findings suggest that template switching constitutes a general mutagenic mechanism that results in both nonsynonymous substitutions and parallel evolution, which are traditionally considered as evidence for positive selection, without the need for adaptive explanations.
Highlights
DNA polymerase template switching between short, non-identical inverted repeats (IRs) is a genetic mechanism that leads to the homogenization of IR arms and to IR spacer inversion, which cause multinucleotide mutations (MNMs)
We looked for cases of MNMs with coordinates overlapping IR arms that mapped to the terminal branch leading to the same strain with the IR (Fig. 1a)
To increase the reliability of the analysis and avoid uncertainty resulting from ancestral sequence reconstruction, focus was placed on MNMs associated with IRs on external branches only
Summary
DNA polymerase template switching between short, non-identical inverted repeats (IRs) is a genetic mechanism that leads to the homogenization of IR arms and to IR spacer inversion, which cause multinucleotide mutations (MNMs). It is unknown if and how template switching affects gene evolution. We determined that template switching introduced MNMs into 39 protein-coding genes through S. cerevisiae evolution, resulting in both arm homogenization and inversion of the IR spacer. These events in turn resulted in nonsynonymous substitutions and up to five neighboring amino acid replacements in a single gene.
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