Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus
Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus
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拷贝数变异 (CNV) 对 HoxD 基因座远程基因调控的影响
DOI：
10.1073/pnas.1217659109
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
D. Duboule
中科院分区：
文献类型：
--
作者：
Thomas Montavon;L. Thevenet;D. Duboule
拷贝数变异是经常与人类疾病相关的基因组结构变异。在这些拷贝数变异中，DNA片段的重复通常被认为通过增加基因或其调控元件的拷贝数而导致剂量效应。我们在鼠HoxD基因座上游的保守基因沙漠中产生了一系列大的靶向重复。该DNA区域与人类2q31 - 32同线，包含Hoxd基因转录所需的一系列调控元件，并且在统称为2q31综合征的人类遗传条件中经常被破坏和/或重组。出乎意料的是，一个这样的重复导致转录下调发育中的数字，通过削弱靶基因和它们的上游调控元件之间的物理相互作用，从而phenocopying当这些增强子序列被删除时获得的效果。这些结果说明了破坏高度保守的调控景观的有害后果，并揭示了基因组重复导致附近基因部分功能丧失的机制。
Copy number variations are genomic structural variants that are frequently associated with human diseases. Among these copy number variations, duplications of DNA segments are often assumed to lead to dosage effects by increasing the copy number of either genes or their regulatory elements. We produced a series of large targeted duplications within a conserved gene desert upstream of the murine HoxD locus. This DNA region, syntenic to human 2q31-32, contains a range of regulatory elements required for Hoxd gene transcription, and it is often disrupted and/or reorganized in human genetic conditions collectively known as the 2q31 syndrome. Unexpectedly, one such duplication led to a transcriptional down-regulation in developing digits by impairing physical interactions between the target genes and their upstream regulatory elements, thus phenocopying the effect obtained when these enhancer sequences are deleted. These results illustrate the detrimental consequences of interrupting highly conserved regulatory landscapes and reveal a mechanism where genomic duplications lead to partial loss of function of nearby located genes.
DOI：
10.1146/annurev.genom.9.081307.164217
发表时间：
2009
影响因子：
8.7
作者：
Zhang F;Gu W;Hurles ME;Lupski JR
通讯作者：
Lupski JR