Mutation at 235th Nucleotide in Mutated Myc Gene Down-Regulates Over-Expression and Cancer Growth: A Computational Genomic Approach

摘要

The work refers to development of computational methodology for characterization of coding sequence of the proto-oncogene Myc present in chromosome 8 of human genome. The mutation at 288th codon where AGC is replaced by AAC results in the substitution of serine to asparagine. This causes over expression of the gene to become an oncogene which ultimately results in uncontrolled tumor formation. A computational methodology has been designed based on Shannon's information theory which mimics the functional weights of the nucleotides. Three parameters, TMIC (Total Modular Information Content), BAI (Binding Affinity Index) and IPCIC (Integrated Per Class Information Content), have been developed to calculate the functional values of the nucleotides. In the process of calculating the parameters, the chemical attribute considered is the partial charge on heteroatoms of A, T, G and C constituting the molecules. The partial charges were calculated using Gaussian software. Two concepts have been utilized in the computational methodology-degeneracy of codons and sensitivity operations of different orders. The IPCIC values of the nucleotides A, T, G and C are 3.84076, 2.8133, 3.2800 and 2.7968 respectively. Using these functional weights of the nucleotides and following 4th order sensitivity operations, the characteristic value of the normal Myc gene was calculated to be 207.1965 and that of the mutated gene was 818.2066. An approach has been initiated by mutating codons following degeneracy principle so that the protein product of the gene is unchanged. The mutation is done at places other than 288th position. Correction of mutated codon at 288th position is not energetically feasible as internal energy of mutated gene is less than that of the normal gene. The mutated Myc gene is more stable than that of the normal gene. The results show that, replacing GGA by GGG at 235th position of mutated Myc gene sequence brings the characteristic value of mutated Myc gene closer to that of normal gene. This gives a strong physical implication that the virulency of the cancerous gene can be reduced to that of the normal gene, thus reducing it's over expression. Such an approach can be employed in cancer research for treatment of cancer for addressing malignant growth. Degeneracy of codons indicates that resolution of mutational effect of gene is not unique. Characteristic value of mutated gene would come to normal/near normal by mono as well as multi point mutational implant. Scope of the work is multivariate. Further studies are in progress.