Data from: Compensatory evolution in RNA secondary structures increases substitution rate variation among sites

There is growing evidence that interactions between biological molecules (e.g., RNA-RNA, protein-protein, RNA-protein) place limits on the rate and trajectory of molecular evolution. Here, by extending Kimura's model of compensatory evolution at interacting sites, we show that the ratio of transition to transversion substitutions (κ) at interacting sites should be equal to the square of the ratio at independent sites. Because transition mutations generally occur at a higher rate than transversions, the model predicts that κ should be higher at interacting sites than at independent sites. We tested this prediction in 10 RNA secondary structures by comparing phylogenetically derived estimates of κ in paired sites within stems (κ(p)) and unpaired sites within loops (κ(u)). Eight of the 10 structures showed an excellent match to the quantitative predictions of the model, and 9 of the 10 structures matched the qualitative prediction κ(p) > κ(u). Only the Rev response element from the human immunovirus (HIV) genome showed the reverse pattern, with κ(p) < κ(u). Although a variety of evolutionary forces could produce quantitative deviations from the model predictions, the reversal in magnitude of κ(p) and κ(u) could be achieved only by violating the model assumption that the underlying transition (or transversion) mutation rates were identical in paired and unpaired regions of the molecule. We explore the ability of the APOBEC3 enzymes, host defense mechanisms against retroviruses, which induce transition mutations preferentially in single-stranded regions of the HIV genome, to explain this exception to the rule. Taken as a whole, our findings suggest that kappa may have utility as a simple diagnostic to evaluate proposed secondary structures.

越来越多的证据表明，生物分子（biological molecules）之间的相互作用（例如RNA-RNA、蛋白质-蛋白质、RNA-蛋白质相互作用）对分子进化的速率与演化轨迹施加了限制。本研究通过拓展木村资生针对相互作用位点的补偿性进化（compensatory evolution）模型，证明了相互作用位点上的转换置换（transition substitutions）与颠换置换（transversion substitutions）的比值（κ）应当等于独立位点上该比值的平方。由于转换突变的发生速率通常高于颠换突变，该模型预测相互作用位点的κ值应当高于独立位点。我们通过比较茎区配对位点（κ(p)）与环区非配对位点（κ(u)）的系统发育推导κ估计值，在10种RNA二级结构（RNA secondary structures）中验证了这一预测。10个结构中有8个与该模型的定量预测高度吻合，9个结构符合κ(p) > κ(u)的定性预测。仅来自人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）基因组的Rev应答元件（Rev response element）呈现出相反模式，即κ(p) < κ(u)。尽管多种进化力量可能导致与模型预测的定量偏差，但κ(p)与κ(u)的大小反转仅能通过违背模型假设实现：该假设认为分子的配对与非配对区域中，基础转换（或颠换）突变速率完全一致。我们探究了APOBEC3酶（APOBEC3 enzymes）——一种诱导HIV基因组单链区域优先发生转换突变的抗逆转录病毒宿主防御机制——能否解释这一规则例外。综合来看，我们的研究结果表明，κ可作为一种简便的诊断手段，用于评估已提出的RNA二级结构。