不同遗传背景下的遗传抑制相互作用高度一致

Claire Paltenghi, Jolanda van Leeuwen
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摘要

当一个有害突变造成的表型缺陷被另一个突变所挽救时,就会发生基因抑制。遗传抑制相互作用对遗传疾病特别重要,因为它们能确定降低疾病严重程度的方法,从而可能为治疗干预提供途径。抑制相互作用在多大程度上受遗传背景的影响,目前仍是一个未知数。然而,高度的抑制保护对于开发针对抑制因子的治疗策略至关重要。为了了解遗传背景对抑制作用的影响,我们在三种不同基因的天然分离芽殖酵母中分离出了对温度敏感的等位基因 SEC17、TAO3 和 GLN1 的自发抑制突变。在确定并验证了导致抑制作用的基因组变异后,我们在所有三种遗传背景以及一个实验室菌株中引入了抑制剂,以评估它们的特异性。在四种酵母菌株中,测试的 11 种抑制相互作用中有 10 种是保守的,尽管抑制因子对温度敏感突变体的拯救程度在不同的遗传背景下有所不同。这些结果表明,抑制机制在不同的遗传背景下是高度保守的,这一发现对开发模拟遗传抑制因子的治疗药物具有潜在的指导意义。
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Genetic suppression interactions are highly conserved across genetic backgrounds
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 three 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 three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four 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.
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