Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance
Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance
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DOI：
10.1086/519248
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发表时间：
2007-08-01
影响因子：
9.8
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
--
作者：
Prandini, Paola;Deutsch, Samuel;Antonarakis, Stylianos E.
唐氏综合征（DS）的特点是广泛的表型变异，大多数性状发生在只有一小部分受影响的个人。在未受影响的个体中存在大量的基因表达变异，并且这种变异具有很强的遗传成分。由于DS是由基因组剂量失衡引起的，我们假设DS患者中人类21号染色体（HSA 21）基因的基因表达变异对受影响个体的表型变异性产生影响。我们研究了14个淋巴母细胞和17个成纤维细胞系的基因表达变异与DS和相同数量的控制个人。使用定量实时聚合酶链反应分别对淋巴母细胞和成纤维细胞系中的100和106个HSA 21基因以及23和26个非HSA 21基因进行基因表达测定。令人惊讶的是，在淋巴母细胞和成纤维细胞中分别只有39%和62%的HSA 21基因显示出DS和正常样品之间的统计学显著差异，尽管在两种细胞类型中HSA 21基因的平均上调接近预期的1.5倍。使用Kolmogorov-Smirnov检验评价DS和正常样本中的基因表达变异。根据表达水平的重叠程度，我们将所有基因分为3组：（A）不重叠，（13）部分重叠，和（C）广泛重叠的表达分布之间的正常和DS样品。我们假设，在每种细胞类型中，A组基因对剂量最敏感，最可能参与恒定DS性状，B组基因可能参与可变DS性状，C组基因对剂量不敏感，最不可能参与DS病理表型。这项研究提供了第一个广泛的数据集HSA 21基因表达变异在DS和强调其在调节基因剂量失衡的结果。
Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (13) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its rote in modulating the outcome of gene-dosage imbalance.