Goldstein Ilan, Hale Joseph J, Ehrenreich Ian M
Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
bioRxiv. 2025 Jun 1:2025.05.28.656710. doi: 10.1101/2025.05.28.656710.
Global epistasis is a phenomenon in which the effects of genetic perturbations depend on the fitness of the individuals in which they occur. In populations with natural genetic variation, global epistasis arises from interactions between perturbations and polymorphic loci that are mediated by fitness. To investigate the prevalence and characteristics of loci involved in these interactions in the budding yeast , we used combinatorial DNA barcode sequencing to measure the fitness of 169 cross progeny (segregants) subjected to 8,126 CRISPRi perturbations across two environments. Global epistasis was evident in these data, with more fit segregants within each environment exhibiting greater sensitivity to genetic perturbations than less fit segregants. We dissected the genetic basis of this global epistasis by scanning the genome for loci whose effects covary with CRISPRi-induced reductions in population fitness. This approach identified 58 loci that interact with fitness, most of which exhibited larger effects in the absence of genetic perturbations. In aggregate, these loci explained the observed global epistasis in each environment and demonstrated that the loci contributing to global epistasis largely overlap with those influencing fitness in unperturbed conditions.
全局上位性是一种现象，其中基因扰动的效应取决于发生这些扰动的个体的适应性。在具有自然遗传变异的群体中，全局上位性源于由适应性介导的扰动与多态位点之间的相互作用。为了研究参与这些相互作用的位点在芽殖酵母中的普遍性和特征，我们使用组合DNA条形码测序来测量169个杂交后代（分离子）在两种环境下受到8126次CRISPRi扰动后的适应性。这些数据中全局上位性很明显，与适应性较差的分离子相比，每个环境中适应性较强的分离子对基因扰动表现出更高的敏感性。我们通过扫描基因组寻找其效应与CRISPRi诱导的群体适应性降低协变的位点，剖析了这种全局上位性的遗传基础。这种方法鉴定出58个与适应性相互作用的位点，其中大多数在没有基因扰动的情况下表现出更大的效应。总体而言，这些位点解释了在每个环境中观察到的全局上位性，并表明导致全局上位性的位点在很大程度上与那些在未受扰动条件下影响适应性的位点重叠。
