Negative genetic regulators of phenotypic heterogeneity, or phenotypic capacitors/stabilizers, elevate population-average fitness by limiting deviation from the optimal phenotype and increase the efficacy of natural selection by enhancing the phenotypic differences among genotypes. Stabilizers can presumably be switched off to release phenotypic heterogeneity in the face of extreme or fluctuating environments to ensure population survival. This task could, however, also be achieved by positive genetic regulators of phenotypic heterogeneity, or “phenotypic diversifiers”, as shown by recently reported evidence that a bacterial divisome factor enhances antibiotic resistance. We hypothesized that such active creation of phenotypic heterogeneity by diversifiers, which is functionally independent of stabilizers, is more common than previously recognized. Using morphological phenotypic data from 4,718 single-gene-knockout strains of Saccharomyces cerevisiae, we systematically identified 324 stabilizers and 160 diversifiers and constructed a bipartite network between these genes and the morphological traits they control. Further analyses showed that, compared with stabilizers, diversifiers tended to be weaker and more promiscuous (regulating more traits) regulators targeting traits unrelated to fitness. Moreover, there is a general division of labor between stabilizers and diversifiers. Finally, by incorporating NCI-60 human cancer cell line anticancer drug screening data, we found that human one-to-one orthologs of yeast diversifiers/stabilizers likely regulate the anticancer drug resistance of human cancer cell lines, suggesting that these orthologs are potential targets for auxiliary treatments. Our study therefore highlights stabilizers and diversifiers as the genetic regulators for the bidirectional control of phenotypic heterogeneity, as well as their distinct evolutionary roles and functional independence.

中文翻译：

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表型异质性的双向遗传控制及其对癌症耐药性的影响

表型异质性的负基因调节剂，或表型电容器/稳定剂，通过限制与最佳表型的偏离来提高群体平均适应度，并通过增强基因型之间的表型差异来提高自然选择的效率。可能会关闭稳定剂以在极端或多变的环境中释放表型异质性，以确保种群生存。然而，这项任务也可以通过表型异质性的积极遗传调节剂或“表型多样化子”来实现，如最近报道的证据表明，细菌分异因子增强了抗生素耐药性。我们假设功能多样化独立于稳定剂的分散剂对表型异质性的主动产生比以前认识到的更为普遍。酿酒酵母，我们系统地鉴定了324种稳定剂和160种多样化子，并在这些基因与它们控制的形态性状之间建立了一个二分网络。进一步的分析表明，与稳定剂相比，多样化剂倾向于针对与健身无关的性状的功能更弱，更混杂（调节更多性状）。此外，稳定器和分散器之间存在一般的分工。最后，通过纳入NCI-60人类癌细胞系抗癌药物筛选数据，我们发现酵母多样化剂/稳定剂的人类一对一直系同源物可能调节了人类癌细胞系的抗癌药耐药性，表明这些直系同源物是潜在的靶标用于辅助治疗。