Université Côte d'Azur, CNRS, INSERM, IRCAN, 06107 Nice, France.
Department of Chemistry and Molecular Biology, University of Gothenburg, 41390 Gothenburg, Sweden.
Genome Res. 2020 May;30(5):697-710. doi: 10.1101/gr.253351.119. Epub 2020 Apr 10.
Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes and We found that massive expansion of intragenic tandem repeats within the N-terminal domain of was sufficient to cause pronounced life span shortening. Life span impairment by was buffered by rapamycin but not by calorie restriction. The repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.
由于遗传和环境的原因，个体的衰老程度各不相同，但潜在的分子机制在很大程度上仍然未知。我们使用高度重组的群体，在富含卡路里和限制卡路里的环境中以及在雷帕霉素暴露下，发现了 30 个不同的控制时序寿命 (CLS) 的数量性状基因座 (QTL)。卡路里限制和雷帕霉素在几乎所有基因型中都延长了寿命，但通过不同的遗传变异。我们追踪了两个主要的 QTL 到细胞壁糖蛋白基因 和 我们发现， 基因 N 端结构域内内含子串联重复的大规模扩增足以导致明显的寿命缩短。雷帕霉素但不是卡路里限制缓冲了 引起的寿命损伤。 重复扩展使酵母细胞从静止状态转变为漂浮状态，从而增加了它们与周围氧气的接触。更高的氧合作用改变了蛋氨酸、脂质和嘌呤代谢，并抑制了静止，这解释了寿命缩短。我们得出结论，快速进化的内含子重复扩展可以从根本上改变细胞与其环境之间的关系，对细胞生活方式和寿命产生深远影响。
