Extreme positive epistasis for fitness in monosomic yeast strains - part 2

The loss of a single chromosome in a diploid organism halves the dosage of many genes and is usually accompanied by a substantial decrease in fitness. We asked whether this decrease simply reflects the joint damage caused by individual gene dosage deficiencies. We measured the fitness effects of single heterozygous gene deletions in yeast and combined them for each chromosome. This predicted a negative growth rate, i.e. lethality, for multiple monosomies. However, monosomic strains remained alive and grew as if much (often most) of the damage caused by single mutations had disappeared, revealing an exceptionally large and positive epistatic component of fitness. We looked for functional explanations by analyzing the transcriptomes. There was no evidence of increased (compensatory) gene expression on the monosomic chromosomes. Nor were there signs of the cellular stress response that would be expected if monosomy led to protein destabilization and thus cytotoxicity. Instead, all monosomic strains showed extensive upregulation of genes encoding ribosomal proteins, but in an indiscriminate manner that did not correspond to their altered dosage. This response did not restore the stoichiometry required for efficient biosynthesis, which probably became growth limiting, making all other mutation-induced metabolic defects much less important. In general, the modular structure of the cell leads to an effective fragmentation of the total mutational load. Defects outside the module(s) currently defining fitness lose at least some of their relevance, producing the epiphenomenon of positive interactions between individually negative effects.在二倍体生物（diploid organism）中，单条染色体（chromosome）的缺失会使众多基因的表达剂量（dosage）减半，通常伴随适合度（fitness）的显著下降。我们希望探明该适合度下降是否仅由单个基因的剂量缺陷共同引发。我们在酵母（yeast）中测定了单个杂合基因缺失（heterozygous gene deletion）对适合度的影响，并针对每条染色体将这些影响进行整合。据此可预测，多染色体单体性（monosomy）会导致生长速率为负，即致死。然而，单染色体菌株仍可存活并增殖，仿佛单个突变引发的大部分损伤已然消失，这揭示出适合度存在异常显著且正向的上位性（epistatic）效应组分。我们通过分析转录组（transcriptome），试图找到其功能层面的解释。单条染色体上并未出现基因表达上调（补偿性表达）的迹象；同时，若单体性引发蛋白质不稳定进而产生细胞毒性，理应观测到细胞应激反应，但也未发现此类信号。与之相反，所有单染色体菌株均出现了编码核糖体蛋白（ribosomal protein）的基因的广泛上调，但这种上调并无选择性，与其剂量变化并不匹配。这种上调并未恢复高效生物合成（biosynthesis）所需的化学计量比（stoichiometry），而这一失衡可能成为生长限制因素，使得其他所有由突变引发的代谢缺陷的重要性大幅降低。总体而言，细胞的模块化结构（modular structure）使得总突变负荷（mutational load）被有效分割。当前定义适合度的模块之外的缺陷，其相关性至少会有所减弱，从而产生单个负效应间存在正向互作的副现象（epiphenomenon）。