MINING GENOME VARIATION TO ASSOCIATE GENETIC DISEASE WITH MUTATION ALTERATIONS AND ORTHO/PARALOGOUS POLIMORPHYSMS IN TRANSCRIPTION FACTOR BINDING SITE

Abstract

We have developed a system rSNP_Guide, , predicting the transcription factor (TF) binding sites on DNA, which mutation-caused alterations may explain disease penetration. rSNP_Guide uses the detected alterations in the mutant DNA binding to unknown TF caused by diseases and, upon the DNA sequences, calculates the alterations in known TF sites so that to select only the known ones with calculated alterations in the best consistence with those detected. Our system has been control tested on the SNP's with known site-disease relationships. For practical aims, two TF sites associated with diseases were predicted and confirmed by the immune assay with anti-TF antibodies. In the case of tumor susceptibility, the GATA site in the second intron of mouse K-ras gene was truly predicted, whereas mutation damage of this site causes tumor resistance. In the case of alcohol dependencies and others behavioral diseases, the mutation-caused spurious YY1 site in the sixth intron of human tryptophan 2,3-dioxygenase (TDO2) gene was successfully predicted. Finally, sixteen non-documented TF sites localizable at both orthologous and paralogous genes were first characterized by three rates "present", "weakened" or "absent", with significance estimated by rSNP_Guide relatively to six TF sites with known mutation-caused alterations in DNA/TF-binding.