Reproduction Genetics, Department of Endocrinology and Infertility Disorders, Women Hospital, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
Department of Radiation Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Am J Hum Genet. 2022 Dec 1;109(12):2126-2140. doi: 10.1016/j.ajhg.2022.10.014.
Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. Although increased expression of the genes localized on the extra chromosome triggers several pathological phenotypes, an alternative model suggests that global, aneuploidy-associated changes in cellular physiology also contribute to the pathology. Here, we compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro. We point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity. This alternative view may provide useful insights for understanding Down syndrome pathology and open additional opportunities for diagnostics and treatments.
染色体获得对人类胚胎的发育是有害的。因此，常染色体三体几乎总是导致自然流产，而极少数存活到出生的胚胎则患有多种病理缺陷。目前尚无治疗方法可以改善三体的后果，例如唐氏综合征（21 号染色体三体）。确定具有额外染色体的细胞中观察到的表型的来源对于理解三体综合征的潜在分子原因至关重要。尽管位于额外染色体上的基因的表达增加引发了几种病理表型，但另一种模型表明，细胞生理学的全基因组、非整倍体相关变化也有助于病理发生。在这里，我们比较了体内三体综合征的分子后果与体外携带各种染色体获得的工程细胞系。我们指出了一些由不同三体共享的表型，因此这些表型可能是由于额外染色体的存在本身引起的，而与染色体的身份无关。这种替代观点可能为理解唐氏综合征的病理提供有用的见解，并为诊断和治疗开辟更多的机会。
