Transcription dosage compensation does not occur in Down syndrome.
Transcription dosage compensation does not occur in Down syndrome.
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DOI：
10.1186/s12915-023-01700-4
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发表时间：
2023-11-10
期刊：
影响因子：
5.4
通讯作者：
Allen, Mary A.
中科院分区：
文献类型：
--
作者：
Hunter, Samuel;Hendrix, Jo;Freeman, Justin;Dowell, Robin D.;Allen, Mary A.
唐氏综合征（DS;由21三体引起）中DNA拷贝数的增加导致了DNA剂量假说，该假说假定基因表达水平与基因的DNA拷贝数成正比。然而，许多报告表明，21号染色体基因的一部分被剂量补偿回到典型的表达水平（1.0×）。相反，其他报告表明，剂量补偿不是21三体的基因调控的常见机制，为DNA剂量假说提供了支持。在我们的工作中，我们使用模拟和真实的数据来剖析差异表达分析的元素，这些元素可以导致剂量补偿的出现，即使补偿明显不存在。使用来自唐氏综合征患者家族的淋巴母细胞系，我们证明了在新生转录（GRO-seq）和稳态RNA（RNA-seq）水平上几乎不存在剂量补偿。此外，我们将有限的表观剂量补偿与预期的转录水平等位基因变异联系起来。唐氏综合征中不发生转录剂量补偿。当通过标准方法分析时，不包含剂量补偿的模拟数据可能会出现剂量补偿。此外，一些21号染色体的基因，似乎是剂量补偿是一致的等位基因特异性表达。在线版本包含补充材料，可通过10.1186/s12915-023-01700-4获得。
The increase in DNA copy number in Down syndrome (DS; caused by trisomy 21) has led to the DNA dosage hypothesis, which posits that the level of gene expression is proportional to the gene’s DNA copy number. Yet many reports have suggested that a proportion of chromosome 21 genes are dosage compensated back towards typical expression levels (1.0×). In contrast, other reports suggest that dosage compensation is not a common mechanism of gene regulation in trisomy 21, providing support to the DNA dosage hypothesis. In our work, we use both simulated and real data to dissect the elements of differential expression analysis that can lead to the appearance of dosage compensation, even when compensation is demonstrably absent. Using lymphoblastoid cell lines derived from a family with an individual with Down syndrome, we demonstrate that dosage compensation is nearly absent at both nascent transcription (GRO-seq) and steady-state RNA (RNA-seq) levels. Furthermore, we link the limited apparent dosage compensation to expected allelic variation in transcription levels. Transcription dosage compensation does not occur in Down syndrome. Simulated data containing no dosage compensation can appear to have dosage compensation when analyzed via standard methods. Moreover, some chromosome 21 genes that appear to be dosage compensated are consistent with allele specific expression. The online version contains supplementary material available at 10.1186/s12915-023-01700-4.
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