Paltenghi Claire, van Leeuwen Jolanda
Center for Integrative Genomics, University of Lausanne, Génopode Building, 1015 Lausanne, Switzerland.
Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States.
G3 (Bethesda). 2025 May 8;15(5). doi: 10.1093/g3journal/jkaf047.
Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature-sensitive alleles of SEC17, TAO3, and GLN1 in 3 genetically diverse natural isolates of the budding yeast Saccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all 3 genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of 11 tested suppression interactions were conserved in the 4 yeast strains, although the extent to which a suppressor could rescue the temperature-sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.
当有害突变引起的表型缺陷被另一个突变挽救时，就会发生基因抑制。抑制相互作用对于遗传疾病尤为重要，因为它们确定了降低疾病严重程度的方法，从而有可能为治疗干预指明途径。抑制相互作用在多大程度上受到其所处遗传背景的影响，目前仍 largely unknown。然而，高度的抑制保守性对于开发针对抑制子的治疗策略至关重要。为了了解遗传背景对抑制的影响，我们在出芽酵母酿酒酵母的3个遗传背景不同的天然分离株中分离了SEC17、TAO3和GLN1温度敏感等位基因的自发抑制突变。在鉴定并验证了导致抑制的基因组变异后，我们将这些抑制子引入所有3种遗传背景以及一个实验室菌株中，以评估它们的特异性。在测试的11种抑制相互作用中，有10种在4种酵母菌株中是保守的，尽管抑制子挽救温度敏感突变体的程度在不同遗传背景中有所不同。这些结果表明，抑制机制在不同遗传背景中高度保守，这一发现对于开发模拟基因抑制子的治疗方法可能是令人安心的。
