Survey of polymorphic sequence variation in the immediate 5' region of human DNA repair genes.

Systematic screens have revealed extensive DNA sequence variation existing in the human population. Studies of the role of polymorphic genetic variants in explaining the association of family history with risk of common disease have generally focused on variants predicted to disrupt protein structure and activity. Recent studies have identified genetic variation in the level of expression of many genes, variation that is potentially biologically relevant in explaining individual variation in disease risk. In a survey of data available for 108 DNA repair genes that have been systematically screened for sequence variation, an average of 3.3 SNPs per gene were found to exist at a variant allele frequency of at least 0.02 in the region 2kb upstream from the 5'-untranslated region. One-third of the genes harbored a SNP with an allele frequency of at least 0.02 within a predicted promotor element. These variants are distributed among promoter elements that average 20 elements per gene. The frequency of polymorphic SNPs in CpG islands was 0.8 per gene, while the frequency of SNPs in the 5'-UTR was 0.7 per gene. The recognition of extensive genetic variation with potential to impact levels of gene expression, and thereby exacerbate the impact of amino acid substitution variants on the activity of proteins, increases the complexity of analyses required to explain the molecular genetic basis for the familial contribution to the sporadic incidence of common disease.