Rivas-Santisteban Juan, Yubero Pablo, Hurst Laurence D
Systems Biology Department, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
Milner Centre for Evolution, Department of Life Sciences, University of Bath, Bath, UK.
Genome Biol Evol. 2025 Jul 3;17(7). doi: 10.1093/gbe/evaf126.
What accounts for the variation between proteins in their rate of evolution per synonymous substitution (i.e. dN/dS, alias ω)? Previous analyses suggested that cell location is predictive, with intracellular proteins evolving slower than membrane proteins, a result considered supportive of the extended complexity hypothesis. However, as they occur in 3D space, cytoplasmic proteins are expected to be more abundant. As the level of gene expression is the strongest predictor of ω, and many predictors of protein rate variation are explained by covariance with it, here we ask whether the cell compartment effect is explained by covariates. We employ two single-celled species for which there exist exceptional data, the bacterium (Escherichia coli) and the eukaryote (Saccharomyces cerevisiae). For both, we establish informative species trios to determine branch-specific ω values. In both species, in the absence of covariate control, cytoplasmic proteins evolve relatively slowly, while membrane proteins evolve fast, as originally claimed. After controlling for protein abundance, however, membrane proteins have the lowest rates, this inversion being resilient to multiple alternative abundance control methods. The effect size of the cell compartment as a predictor is of a comparable magnitude to the essentiality effect and remains when allowing for essentiality. We conclude that the effects of the cell compartments are real, but their direction is dependent on the presence or absence of abundance control. These results question any model, such as the extended complexity hypothesis, that claims support from a slower evolution of cytoplasmic proteins and underscore the importance of covariate control.
是什么导致了蛋白质在每个同义替换的进化速率（即dN/dS，别名ω）上存在差异？先前的分析表明，细胞定位具有预测性，细胞内蛋白质的进化速度比膜蛋白慢，这一结果被认为支持扩展复杂性假说。然而，由于它们存在于三维空间中，预计细胞质蛋白更为丰富。由于基因表达水平是ω的最强预测因子，并且许多蛋白质速率变化的预测因子都可以通过与其的协方差来解释，因此我们在此询问细胞区室效应是否可以由协变量来解释。我们采用了两种拥有特殊数据的单细胞物种，即细菌（大肠杆菌）和真核生物（酿酒酵母）。对于这两种物种，我们建立了信息丰富的物种三联体来确定特定分支的ω值。在这两种物种中，在没有协变量控制的情况下，细胞质蛋白进化相对较慢，而膜蛋白进化较快，正如最初所声称的那样。然而，在控制了蛋白质丰度之后，膜蛋白的进化速率最低，这种反转对多种替代丰度控制方法具有抗性。作为预测因子的细胞区室的效应大小与必需性效应相当，并且在考虑必需性时仍然存在。我们得出结论，细胞区室的效应是真实的，但其方向取决于是否存在丰度控制。这些结果对任何声称从细胞质蛋白进化较慢中获得支持的模型（如扩展复杂性假说）提出了质疑，并强调了协变量控制的重要性。
