Beach Rebecca R, Ricci-Tam Chiara, Brennan Christopher M, Moomau Christine A, Hsu Pei-Hsin, Hua Bo, Silberman Rebecca E, Springer Michael, Amon Angelika
David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2017 Apr 6;169(2):229-242.e21. doi: 10.1016/j.cell.2017.03.021.
Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.
表型变异性是涉及染色体增减的疾病的一个标志，如唐氏综合征和癌症。等位基因变异一直被认为是这种异质性的唯一原因。在这里，我们系统地研究了单条或多条染色体增减的后果，以表明非整倍体状态会导致非遗传表型变异性。携带相同定义的非整倍体的酵母细胞群体在细胞周期进程和对环境扰动的反应中表现出异质性。变异性随着非整倍体程度的增加而增加，部分原因是基因拷贝数失衡，这表明基因表达的细微变化会影响生物网络的稳健性，并在多个基因中发生时导致不同的行为。由于近交三体小鼠也表现出可变的表型，我们进一步提出，非遗传个体性是非整倍体状态的一个普遍特征，可能导致由非整倍体引起的疾病在表现和治疗反应上的变异性。
