Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar J M, Potier M-C
Neurobiologie et Diversité Cellulaire, Unité Mixte de Recherche 7637 du Centre National de la Recherche Scientifique et de l'Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, France.
Am J Hum Genet. 2007 Sep;81(3):475-91. doi: 10.1086/520000. Epub 2007 Jul 19.
Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance. Variations in chromosome 21 gene expression in Down syndrome were analyzed in lymphoblastoid cells derived from patients and control individuals. Of the 359 genes and predictions displayed on a specifically designed high-content chromosome 21 microarray, one-third were expressed in lymphoblastoid cells. We performed a mixed-model analysis of variance to find genes that are differentially expressed in Down syndrome independent of sex and interindividual variations. In addition, we identified genes with variations between Down syndrome and control samples that were significantly different from the gene-dosage effect (1.5). Microarray data were validated by quantitative polymerase chain reaction. We found that 29% of the expressed chromosome 21 transcripts are overexpressed in Down syndrome and correspond to either genes or open reading frames. Among these, 22% are increased proportional to the gene-dosage effect, and 7% are amplified. The other 71% of expressed sequences are either compensated (56%, with a large proportion of predicted genes and antisense transcripts) or highly variable among individuals (15%). Thus, most of the chromosome 21 transcripts are compensated for the gene-dosage effect. Overexpressed genes are likely to be involved in the Down syndrome phenotype, in contrast to the compensated genes. Highly variable genes could account for phenotypic variations observed in patients. Finally, we show that alternative transcripts belonging to the same gene are similarly regulated in Down syndrome but sense and antisense transcripts are not.
由21号染色体三体导致的唐氏综合征是人类智力发育迟缓最常见的遗传病因。表型的破坏被认为是基因剂量失衡的结果。对来自患者和对照个体的淋巴母细胞中21号染色体基因表达的变化进行了分析。在专门设计的高内涵21号染色体微阵列上展示的359个基因及预测序列中，三分之一在淋巴母细胞中表达。我们进行了方差混合模型分析，以寻找在唐氏综合征中独立于性别和个体间差异而差异表达的基因。此外，我们鉴定出唐氏综合征与对照样本之间存在差异且与基因剂量效应（1.5）显著不同的基因。微阵列数据通过定量聚合酶链反应进行验证。我们发现，21号染色体上29%的表达转录本在唐氏综合征中过度表达，对应于基因或开放阅读框。其中，22%与基因剂量效应成比例增加，7%被扩增。其他71%的表达序列要么得到补偿（56%，其中大部分是预测基因和反义转录本），要么在个体间高度可变（15%）。因此，21号染色体上的大多数转录本对基因剂量效应进行了补偿。与得到补偿的基因相反，过度表达的基因可能与唐氏综合征表型有关。高度可变的基因可能解释了患者中观察到的表型变异。最后，我们表明，属于同一基因的可变转录本在唐氏综合征中受到类似调控，但正义和反义转录本则不然。
