Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Nature. 2022 Jun;606(7915):725-731. doi: 10.1038/s41586-022-04823-w. Epub 2022 Jun 8.
Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral. Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes with diverse functions and expression levels and measured their fitness relative to the wild type in a rich medium. Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar-albeit nonidentical-between synonymous and nonsynonymous mutations. Both synonymous and nonsynonymous mutations frequently disturbed the level of mRNA expression of the mutated gene, and the extent of the disturbance partially predicted the fitness effect. Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates. The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synoymous mutations are neutral.
同义突变不会改变蛋白质序列，因此通常被认为是中性或近中性的。为了验证这一假设，我们构建了 8341 个酵母突变体，每个突变体在 21 个具有不同功能和表达水平的内源性基因中的一个基因中携带同义、非同义或无义突变，并在丰富的培养基中测量它们相对于野生型的适应度。四分之三的同义突变导致适应度显著降低，并且同义和非同义突变之间的适应度效应分布总体上相似（尽管不完全相同）。同义和非同义突变都经常干扰突变基因的 mRNA 表达水平，并且干扰的程度部分预测了适应度效应。在其他环境中的研究表明，尽管在每种环境中的适应度分布相似，但非同义突变体的跨环境适应度变化比同义突变体更大，这表明在不断变化的环境中，非致死性的非同义突变体的比例比同义突变体小，从而允许固定，这可能解释了在其他基因和其他生物体中观察到的明显低于同义取代率的非同义取代率的常见现象。如果大多数同义突变确实具有这种强烈的非中性特征，那么这将需要重新审视许多关于突变、选择、有效种群大小、分歧时间和疾病机制的生物学结论，这些结论都依赖于同义突变是中性的假设。
