Bidirectional Genetic Control of Phenotypic Heterogeneity and Its Implication for Cancer Drug Resistance.
Bidirectional Genetic Control of Phenotypic Heterogeneity and Its Implication for Cancer Drug Resistance.
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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
DOI：
10.1093/molbev/msaa332
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发表时间：
2021-05-04
影响因子：
10.7
通讯作者：
Yang JR
中科院分区：
文献类型：
--
作者：
Mo N;Zhang X;Shi W;Yu G;Chen X;Yang JR
表型异质性的负性遗传调控因子或表型电容器/稳定器通过限制对最优表型的偏离来提高种群的平均适应度，并通过增强基因型间的表型差异来提高自然选择的效率。在极端或波动的环境中，稳定器可能被关闭以释放表型异质性，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“表型多样化剂”来实现，正如最近报道的证据所表明的那样，细菌分裂因子增强了抗生素耐药性。我们假设，这种由多样化者主动创造的表型异质性，其功能独立于稳定剂，比以前认识到的更为普遍。利用4718株酿酒酵母单基因敲除菌株的形态表型数据，系统鉴定出324个稳定因子和160个多样化因子，并构建了这些基因与其控制的形态性状之间的双部网络。进一步的分析表明，与稳定因子相比，多样化因子倾向于更弱和更混杂（调节更多的性状），调节剂针对与适合度无关的性状。此外，在稳定器和多样化器之间存在一般的分工。最后，通过结合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同源物可能调节人类癌细胞系的抗癌药物耐药性，这表明这些同源物是辅助治疗的潜在靶点。因此，我们的研究强调了稳定剂和多样化剂作为表型异质性双向控制的遗传调节剂，以及它们独特的进化作用和功能独立性。
Abstract 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.
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影响因子：
2.9
作者：
Luo Y;Na Z;Slavoff SA
通讯作者：
Slavoff SA
影响因子：
4.3
作者：
Chen X;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Garmendia-Torres C;Skupin A;Michael SA;Ruusuvuori P;Kuwada NJ;Falconnet D;Cary GA;Hansen C;Wiggins PA;Dudley AM
通讯作者：
Dudley AM
影响因子：
9.8
作者：
Levy, Sasha F.;Siegal, Mark L.
通讯作者：
Siegal, Mark L.
影响因子：
11.2
作者：
Reinhold WC;Sunshine M;Liu H;Varma S;Kohn KW;Morris J;Doroshow J;Pommier Y
通讯作者：
Pommier Y