Understanding the Dynamics of Gene Regulatory Systems; Characterisation and Clinical Relevance of cis-Regulatory Polymorphisms.
Understanding the Dynamics of Gene Regulatory Systems; Characterisation and Clinical Relevance of cis-Regulatory Polymorphisms.
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DOI：
10.3390/biology2010064
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发表时间：
2013-01-09
期刊：
影响因子：
4.2
通讯作者：
MacKenzie A
中科院分区：
文献类型：
--
作者：
Cowie P;Ross R;MacKenzie A
现代遗传分析表明，大多数与人类疾病相关的多态性都是非编码的。非编码基因组中包含的许多功能信息由顺式调控序列（CRS）组成，这些序列是对指导细胞特异性基因表达的信号转导线索做出反应所必需的。据推测，许多疾病可能是由于 CRS 内的多态性改变了它们对信号转导线索的反应所致。然而，CRS 的鉴定以及等位基因变异对其响应信号转导线索的能力的影响仍处于早期阶段。在当前的综述中，我们描述了基于 ENCODE 联盟最新进展的比较基因组学和实验技术的使用，这些技术可以识别 CRS。此外，我们还描述了可分析等位基因变异和表观遗传修饰对 CRS 对信号转导线索的反应的影响的技术。通过具体的例子，我们表明驱动这些元素的相互作用是高度复杂的，并且与疾病相关的多态性的影响通常是微妙的。显然，了解 CRS 的功能以及它们如何受到 SNP 和表观遗传修饰的影响，对于了解人类疾病和分层的遗传基础至关重要，同时为个性化医疗的发展提供新的方向。
Modern genetic analysis has shown that most polymorphisms associated with human disease are non-coding. Much of the functional information contained in the non-coding genome consists of cis-regulatory sequences (CRSs) that are required to respond to signal transduction cues that direct cell specific gene expression. It has been hypothesised that many diseases may be due to polymorphisms within CRSs that alter their responses to signal transduction cues. However, identification of CRSs, and the effects of allelic variation on their ability to respond to signal transduction cues, is still at an early stage. In the current review we describe the use of comparative genomics and experimental techniques that allow for the identification of CRSs building on recent advances by the ENCODE consortium. In addition we describe techniques that allow for the analysis of the effects of allelic variation and epigenetic modification on CRS responses to signal transduction cues. Using specific examples we show that the interactions driving these elements are highly complex and the effects of disease associated polymorphisms often subtle. It is clear that gaining an understanding of the functions of CRSs, and how they are affected by SNPs and epigenetic modification, is essential to understanding the genetic basis of human disease and stratification whilst providing novel directions for the development of personalised medicine.