School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, AB25 2ZD, UK.
Biology (Basel). 2013 Jan 9;2(1):64-84. doi: 10.3390/biology2010064.
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.
现代遗传分析表明，大多数与人类疾病相关的多态性是非编码的。非编码基因组中包含的许多功能信息都由顺式调控序列（CRS）组成，这些序列是响应信号转导线索所必需的，这些线索指导细胞特异性基因表达。有人假设，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。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，我们描述了使用比较基因组学和实验技术来识别 CRS，这些技术是基于 ENCODE 联盟的最新进展。此外，我们还描述了分析等位基因变异和表观遗传修饰对 CRS 响应信号转导线索的影响的技术。通过具体示例，我们表明驱动这些元件的相互作用非常复杂，与疾病相关的多态性的影响通常很微妙。显然，了解 CRS 的功能以及 SNP 和表观遗传修饰如何影响它们，对于理解人类疾病的遗传基础和分层至关重要，同时为个性化医疗的发展提供了新的方向。
