Supplementary Material for: Specific transcriptional changes in human fetuses with autosomal trisomies

Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effect due to the trisomic chromosome a genome-wide transcriptional dysregulation has been postulated. The aim of this study was to define the transcriptional changes in trisomy 13, 18, and 21 during early fetal development in order to obtain more insights into the molecular etiopathology of aneuploidy. Using oligonucleotide microarrays, we analyzed whole genome expression profiles in cultured amniocytes (AC) and chorionic villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 13, 18 and 21. We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional levels of most of the genes on the supernumerary chromosome appeared similar to the respective chromosomal pair in normal karyotypes. A subset of chromosome 21 genes including the DSCR1 gene involved in fetal heart development was consistently up-regulated in different prenatal tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 18 vigorous downstream transcriptional changes were found. Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses.

在所有完全性常染色体三体（autosomal trisomy）中，仅21号染色体三体（唐氏综合征，Down syndrome）、18号染色体三体（爱德华兹综合征，Edwards syndrome）与13号染色体三体（帕陶综合征，Patau syndrome）患者可存活至产后阶段。但额外染色体（supernumerary chromosome）如何扰乱正常发育并引发特异性表型（phenotype）的具体机制，目前仍未完全阐明。针对三体染色体引发的基因剂量效应（gene dosage effect），学界已提出全基因组转录失调（genome-wide transcriptional dysregulation）这一替代假说。本研究旨在明确13、18、21号染色体三体在早期胎儿发育过程中的转录变化，以期深入解析非整倍体（aneuploidy）的分子发病机制。本研究采用寡核苷酸微阵列（oligonucleotide microarray）技术，对核型正常以及携带13、18、21号染色体三体的妊娠样本的培养羊水细胞（amniocytes，缩写AC）与绒毛膜绒毛细胞（chorionic villus cells，缩写CV）开展了全基因组表达谱（whole genome expression profiles）分析。结果显示，三体染色体上的部分基因呈现轻度至中度的上调表达；额外染色体上多数基因的转录水平，与正常核型中对应的同源染色体基因对的转录水平基本一致。其中，包括参与胎儿心脏发育的DSCR1基因在内的部分21号染色体基因，在21三体胎儿的不同产前组织（AC、CV）中均呈现稳定上调；而其余所有染色体的基因仅发生微小表达变化。与之相反，18三体样本中则观察到显著的下游转录组（transcriptome）变化。针对13、18、21号常染色体三体的全转录组分析结果，支持上述两大假说的联合作用机制。