The importance and identification of regulatory polymorphisms and their mechanisms of action

The search for the genetic variations underlying all human phenotypes is in its infancy but must be one of the long term goals of the scientific community. There is evidence that most, if not all human phenotypes, including illnesses are influenced by the genetic makeup of the individual. There are an estimated 11 million human genetic polymorphisms with a minor allele frequency >1% and possibly many times that number of rare sequence variants. The proportion of these sequence variants which have any functional effect is unknown but it is likely that the majority of those which influence illness lie outside of the amino acid coding regions of genes, and affect the regulation of gene expression—these are called rSNPs. Recent research suggests that about 50% of genes have one or more common rSNPs associated with them and probably most if not all genes have an rSNP within the human population. In the long term, determining which polymorphisms are potentially functional must be done bio-informatically using algorithms based upon experimental data. However, at the current time, the limited data that has been obtained does not allow the creation of such an algorithm. In vitro studies suggest that a large proportion of rSNPs lie within the core and proximal promoter regions of genes but it is not clear how the majority of these influence transcription, as they do not appear to be within any known transcription factor binding sites. However, promoter regions possess a number of sequence-dependent characteristics which make them distinct from the rest of the genome, namely stability, curvature and flexibility. Subtle changes to these features may underlie the mechanisms by which many polymorphisms exert their function