Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA, 90089, USA.
SLAC National Accelerator Laboratory, Menlo Park, CA, 94025, USA.
Nat Commun. 2024 May 18;15(1):4234. doi: 10.1038/s41467-024-48626-1.
Interactions between genetic perturbations and segregating loci can cause perturbations to show different phenotypic effects across genetically distinct individuals. To study these interactions on a genome scale in many individuals, we used combinatorial DNA barcode sequencing to measure the fitness effects of 8046 CRISPRi perturbations targeting 1721 distinct genes in 169 yeast cross progeny (or segregants). We identified 460 genes whose perturbation has different effects across segregants. Several factors caused perturbations to show variable effects, including baseline segregant fitness, the mean effect of a perturbation across segregants, and interacting loci. We mapped 234 interacting loci and found four hub loci that interact with many different perturbations. Perturbations that interact with a given hub exhibit similar epistatic relationships with the hub and show enrichment for cellular processes that may mediate these interactions. These results suggest that an individual's response to perturbations is shaped by a network of perturbation-locus interactions that cannot be measured by approaches that examine perturbations or natural variation alone.
遗传干扰和分离位点之间的相互作用可能导致干扰在遗传上不同的个体中表现出不同的表型效应。为了在许多个体中在基因组范围内研究这些相互作用，我们使用组合 DNA 条码测序来测量针对 1721 个不同基因的 8046 个 CRISPRi 干扰在 169 个酵母杂交后代（或分离子）中的适应度效应。我们鉴定了 460 个基因，其干扰在分离子中表现出不同的效应。几个因素导致干扰表现出可变的效应，包括基线分离子适应度、干扰在分离子中的平均效应以及相互作用的位点。我们绘制了 234 个相互作用的位点，发现了四个与许多不同干扰相互作用的枢纽位点。与给定枢纽相互作用的干扰与枢纽表现出相似的上位性关系，并富集了可能介导这些相互作用的细胞过程。这些结果表明，个体对干扰的反应是由一个由干扰-基因相互作用组成的网络塑造的，而仅通过检查干扰或自然变异的方法无法测量该网络。
