Institute of Information Science, Academia Sinica, Taipei 115, Taiwan.
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
Nucleic Acids Res. 2021 Jul 21;49(13):7318-7329. doi: 10.1093/nar/gkab555.
Integrating omics data with quantification of biological traits provides unparalleled opportunities for discovery of genetic regulators by in silico inference. However, current approaches to analyze genetic-perturbation screens are limited by their reliance on annotation libraries for prioritization of hits and subsequent targeted experimentation. Here, we present iTARGEX (identification of Trait-Associated Regulatory Genes via mixture regression using EXpectation maximization), an association framework with no requirement of a priori knowledge of gene function. After creating this tool, we used it to test associations between gene expression profiles and two biological traits in single-gene deletion budding yeast mutants, including transcription homeostasis during S phase and global protein turnover. For each trait, we discovered novel regulators without prior functional annotations. The functional effects of the novel candidates were then validated experimentally, providing solid evidence for their roles in the respective traits. Hence, we conclude that iTARGEX can reliably identify novel factors involved in given biological traits. As such, it is capable of converting genome-wide observations into causal gene function predictions. Further application of iTARGEX in other contexts is expected to facilitate the discovery of new regulators and provide observations for novel mechanistic hypotheses regarding different biological traits and phenotypes.
将组学数据与生物特征的定量分析相结合，通过计算机推理为发现遗传调控因子提供了前所未有的机会。然而，目前分析遗传干扰筛选的方法受到其对注释库的依赖的限制，这些注释库用于对命中结果进行优先级排序和随后的靶向实验。在这里，我们提出了 iTARGEX（通过使用期望最大化的混合回归识别与性状相关的调节基因），这是一种关联框架，不需要基因功能的先验知识。在创建了这个工具之后，我们使用它来测试单基因缺失芽殖酵母突变体中基因表达谱与两种生物特征之间的关联，包括 S 期转录组稳态和全局蛋白质周转。对于每种性状，我们发现了以前没有功能注释的新调控因子。然后通过实验验证了新候选物的功能效应，为它们在各自性状中的作用提供了确凿的证据。因此，我们得出结论，iTARGEX 可以可靠地识别与特定生物特征相关的新因子。因此，它能够将全基因组观察结果转化为因果基因功能预测。预计 iTARGEX 在其他情况下的进一步应用将有助于发现新的调控因子，并为不同生物特征和表型的新机制假设提供观察结果。
