A central question in genetics and evolution is the extent to which the outcomes of mutations change depending on the genetic context in which they occur1–3. Pairwise interactions between mutations have been systematically mapped within4–18 and between19 genes, and have been shown to contribute substantially to phenotypic variation among individuals20. However, the extent to which genetic interactions themselves are stable or dynamic across genotypes is unclear21, 22. Here we quantify more than 45,000 genetic interactions between the same 87 pairs of mutations across more than 500 closely related genotypes of a yeast tRNA. Notably, all pairs of mutations interacted in at least 9% of genetic backgrounds and all pairs switched from interacting positively to interacting negatively in different genotypes (false discovery rate < 0.1). Higher-order interactions are also abundant and dynamic across genotypes. The epistasis in this tRNA means that all individual mutations switch from detrimental to beneficial, even in closely related genotypes. As a consequence, accurate genetic prediction requires mutation effects to be measured across different genetic backgrounds and the use of higher-order epistatic terms.Mutagenesis of a yeast tRNA shows that the effects of mutations and how they interact varies both in magnitude and sign between genotypes.

中文翻译：

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tRNA进化过程中的成对和高阶遗传相互作用

遗传学和进化的一个核心问题是突变的结果在多大程度上取决于它们发生的遗传背景1-3。突变之间的成对相互作用已被系统地映射到 4-18 和 19 基因之间，并且已被证明对个体之间的表型变异有很大贡献。然而，基因型之间的遗传相互作用本身在多大程度上是稳定或动态的尚不清楚21、22。在这里，我们量化了酵母 tRNA 的 500 多个密切相关基因型中相同的 87 对突变之间的 45,000 多个遗传相互作用。值得注意的是，所有突变对在至少 9% 的遗传背景中相互作用，并且所有突变对在不同基因型中从正相互作用转变为负相互作用（错误发现率 < 0.1）。跨基因型的高阶相互作用也是丰富和动态的。这种 tRNA 中的上位性意味着所有个体突变都从有害转变为有益，即使在密切相关的基因型中也是如此。因此，准确的遗传预测需要在不同遗传背景下测量突变效应并使用更高阶的上位术语。酵母 tRNA 的诱变表明，突变的影响以及它们如何相互作用在基因型之间的大小和符号上都有所不同.