Exploring the effects of polymorphisms on cis-regulatory signal transduction response.
Bottom Line: cis-Regulatory sequences (CRSs) direct cell-specific and inducible gene expression in response to signal transduction networks, and it is becoming apparent that many cases of disease susceptibility and drug response stratification are due to polymorphisms that alter CRS responses in a context-dependent manner.The technologies described build on the successes of ENCODE (ENCyclopedia Of DNA Elements) by exploring the effects of polymorphisms on CRS context dependency.This understanding is essential to uncover the genomic basis of disease susceptibility and will play a major role in delivering on the promise of personalized medicine.
Affiliation: Gene Regulatory Systems Laboratory, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland AB25 2ZD, UK. email@example.comShow MeSH
Mentions: Meta-analyses of multiple genome wide association (GWA) (see Glossary) studies have shown that 88% of disease-associated single nucleotide polymorphisms (SNPs) are found within intronic or intergenic DNA [1,2], and GWA studies designed to detect the causes of drug response stratification  or unwanted side effects suggest a major role for intronic and intergenic variations [4–8]. Although many of these characteristics are associated with nonfunctional SNPs, many of these sequence differences occur within genomic regions of strong linkage disequilibrium (LD) that contain functional SNPs, the majority of which are noncoding . Furthermore, a large proportion of GWA study hits are found within gene deserts that contain no genes, suggesting a role for long-distance gene regulation in disease. By describing the human regulatory landscape in unprecedented detail using many different cell culture studies, the ENCODE (ENCyclopedia Of DNA Elements) consortium have thrown down the gauntlet to biologists to determine the regulatory causes of diseases [10–13]. The next step in this process is to consider how polymorphic variation within the cis-regulatory genome alters its activity in response to signal transduction cues that represent the most important step in the transfer of biological information from the cell surface to the genome (Figure 1).
Affiliation: Gene Regulatory Systems Laboratory, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland AB25 2ZD, UK. firstname.lastname@example.org