Defining the Role of Single Nucleotide Polymorphic (SNP) in Drug Development and Toxicityc

Abstract

The sequencing of human genome has lead to define the variations among humans, which is quite astonishing. Before sequencing of human genome, variant among genes were observed as mutations. It was known that mutations in key regulatory and functional genes cause diseases. With the advent of single nucleotide polymorphism (SNP) among genes, which is believed to be present in every 1.0 kb in human genome (3X10 6 SNP in 3X10 9 bps genome), has changed the very paradigm of disease progression, drug action and toxicity. Before sequencing of the human genome, such variations were thought far less to exist. Although SNPs are found every 1.0 kb sequence but they are not uniformly distributed. In addition to be present in regulatory sequences, SNPs are found in introns and intergenic sequences. Determining the effects of these variants on biological process is a daunting task. Utilizing the modern molecular biological techniques, the role(s) of the regulatory SNPs has been defined for many genes. However, the structural SNPs, which are part of the coding sequences of genes, have been difficult to define. Models to describe the messenger RNA stability (Mfold analysis) due to such SNPs are welcome and can be used to define mRNA stability. However, such a correlation in terms of end product as protein is still confusing. Attempts have been made to decipher the gene function of individual SNP variant what is referred as “allelic expression variant” of haplotype as compared to wild type. In this context it is noteworthy that allelic variants have been found to possess varying activities. In addition to SNPs, multinucleotide polymorphism in terms of double nucleotide polymorphism (DNPs) and triple nucleotide polymorphism (TNPs) have also been observed in human genome. Frequency of DNPs and TNPs are far less as compare to SNPs. Comparison of DNPs and TNPs from Chinese and Venter data demonstrate that a total of 164 in Chinese and 127 in Venter as DNPs were found. A far less TNPs (3 with Chinese and 6 with Venter genome) were found. It is predicted that SNPs leads to nonsynonimous substitution with 50-50 occurrence while DNPs cause higher nonsynonimous substitutions. DNPs are predicted to convert stop codon into read through codon but both Chinese and Venture genome did not possess any read through DNPs [1].