Understanding the Dynamics of Gene Regulatory Systems: Characterisation and Clinical Relevance of cis-Regulatory Polymorphisms

Philip David Cowie, Alasdair MacKenzie, Ruth Ross

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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.
Original languageEnglish
Pages (from-to)64-84
Number of pages20
Issue number1
Publication statusPublished - 9 Jan 2013



  • gene regulation
  • cis-regulatory variation
  • non-coding DNA
  • chromatin
  • signal transduction
  • drug response stratification
  • cell specificity
  • context dependency
  • ENCODE consortium

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