single nucleotide polymorphisms can create alternative polyadenylation signals and affect gene expression through loss of microrna-regulation单核苷酸多态性可以创建可变聚腺苷酸化信号和通过microrna-regulation损失影响基因表达.pdfVIP

Single Nucleotide Polymorphisms Can Create Alternative Polyadenylation Signals and Affect Gene Expression through Loss of MicroRNA-Regulation 1,2 ˚ 1,2,3 Laurent F. Thomas , Pal Sætrom * 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway, 2 Interagon AS, Laboratoriesenteret, Trondheim, Norway, 3 Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway Abstract Alternative polyadenylation (APA) can for example occur when a protein-coding gene has several polyadenylation (polyA) signals in its last exon, resulting in messenger RNAs (mRNAs) with different 39 untranslated region (UTR) lengths. Different 39UTR lengths can give different microRNA (miRNA) regulation such that shortened transcripts have increased expression. The APA process is part of human cells’ natural regulatory processes, but APA also seems to play an important role in many human diseases. Although altered APA in disease can have many causes, we reasoned that mutations in DNA elements that are important for the polyA process, such as the polyA signal and the downstream GU-rich region, can be one important mechanism. To test this hypothesis, we identified single nucleotide polymorphisms (SNPs) that can create or disrupt APA signals (APA-SNPs). By using a data-integrative approach, we show that APA-SNPs can affect 39UTR length, miRNA regulation, and mRNA expression—both between homozygote individuals and within heterozygote individuals. Furthermore, we show that a significant fraction of the alleles that cause APA are strongly and positively linked with alleles found by genome-wide studies to be associated with disease. Our results co