Systematic analysis of complex genetic interactions

To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.

为系统性探究复杂遗传互作，我们构建了约20万个酵母三重突变体，并完成了负三向遗传互作（negative trigenic interactions）的评分检测。我们选取了覆盖广泛生物学过程的双突变查询基因，这些基因涵盖了全局双基因互作网络（digenic interaction network）的一系列量化特征，并检测其与第三个突变之间的遗传互作。三向遗传互作（trigenic interactions）常发生在功能相关的基因之间，且必需基因是该三向互作网络中的枢纽节点。尽管三向遗传互作存在功能富集现象，但它们往往连接着参与远缘生物学过程的基因，且其互作强度弱于双基因互作（digenic interactions）。我们估算，全局三向遗传互作网络的规模约为全局双基因互作网络的100倍，这凸显了复杂遗传互作有望影响遗传生物学——包括基因型-表型关联（genotype-to-phenotype relationship）——的潜力。