Single-nucleotide polymorphisms can cause different structural folds of mRNA

Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. Genes containing one or more SNPs can give rise to two or more allelic forms of mRNAs. These mRNA variants may possess different bio logical functions as a result of differences in primary or higher order str uctures that interact with other cellular components. Here we report the ob servation of marked differences in mRNA secondary structure associated with SNPs in the coding regions of two human mRNAs: alanyl tRNA synthetase and replication protein A, 70-kDa subunit (RPA70). Enzymatic probing of SNP-con taining allelic fragments of the mRNAs revealed pronounced allelic differen ces in cleavage pattern at sites 14 or 18 nt away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. B y using phosphorothioate oligodeoxyribonucleotides complementary to the reg ion of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself we find that the SNP exerts an allele-specific effect on th e accessibility of its flanking site in the endogenous human RPA70 mRNA. Th is further supports the allele-specific structural features identified by e nzymatic probing. These results demonstrate the contribution of common gene tic variation to structural diversity of mRNA and suggest a broader role th an previously thought for the effects of SNPs on mRNA structure and, ultima tely, biological function.