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- Title
Systematic identification of functional SNPs interrupting 3'UTR polyadenylation signals.
- Authors
Shulman, Eldad David; Elkon, Ran
- Abstract
Alternative polyadenylation (APA) is emerging as a widespread regulatory layer since the majority of human protein-coding genes contain several polyadenylation (p(A)) sites in their 3'UTRs. By generating isoforms with different 3'UTR length, APA potentially affects mRNA stability, translation efficiency, nuclear export, and cellular localization. Polyadenylation sites are regulated by adjacent RNA cis-regulatory elements, the principals among them are the polyadenylation signal (PAS) AAUAAA and its main variant AUUAAA, typically located ~20-nt upstream of the p(A) site. Mutations in PAS and other auxiliary poly(A) cis-elements in the 3'UTR of several genes have been shown to cause human Mendelian diseases, and to date, only a few common SNPs that regulate APA were associated with complex diseases. Here, we systematically searched for SNPs that affect gene expression and human traits by modulation of 3'UTR APA. First, focusing on the variants most likely to exert the strongest effect, we identified 2,305 SNPs that interrupt the canonical PAS or its main variant. Implementing pA-QTL tests using GTEx RNA-seq data, we identified 330 PAS SNPs (called PAS pA-QTLs) that were significantly associated with the usage of their p(A) site. As expected, PAS-interrupting alleles were mostly linked with decreased cleavage at their p(A) site and the consequential 3'UTR lengthening. However, interestingly, in ~10% of the cases, the PAS-interrupting allele was associated with increased usage of an upstream p(A) site and 3'UTR shortening. As an indication of the functional effects of these PAS pA-QTLs on gene expression and complex human traits, we observed for few dozens of them marked colocalization with eQTL and/or GWAS signals. The PAS-interrupting alleles linked with 3'UTR lengthening were also strongly associated with decreased gene expression, indicating that shorter isoforms generated by APA are generally more stable than longer ones. Last, we carried out an extended, genome-wide analysis of 3'UTR variants and detected thousands of additional pA-QTLs having weaker effects compared to the PAS pA-QTLs. Author summary: mRNA molecules that encode for proteins end with a long stretch of adenosines, called poly(A) tail. The poly(A) tail contributes to the stability of the mRNA molecules, their translation to proteins and their import from the nucleus to the cytoplasm. The process of adding this tail to the mRNAs is called polyadenylation, and the termination site on the mRNAs at which the poly(A) tail is added is called the poly(A) site. In recent years it became evident that the vast majority of mRNAs of human genes contain several alternative poly(A) sites and their usage generates different mRNA isoforms that differ in their stability and translation efficiency. Therefore, alternative polyadenylation (APA) is emerging as a novel and important, yet underexplored, mechanism that regulate gene expression. The choice between alternative p(A) sites in an mRNA molecule is regulated by regulatory sequences located within a region in the mRNA called the 3' untranslated region (3'UTR). A major challenge in present human genetics research is to understand how common genetic variants affect individuals' health. In our study, we systematically identified dozens of genetic variants that affect the choice between alternative p(A) sites and demonstrated that by that, these variants influence the expression level of the target genes. Our results help to illuminate a novel mechanism by which genetic variants that are common in the population affect different traits including our risk for developing diseases.
- Subjects
GENE expression; HUMAN genes; CIS-regulatory elements (Genetics); HUMAN genetics; MESSENGER RNA; HUMAN experimentation; ALLELES
- Publication
PLoS Genetics, 2020, Vol 16, Issue 8, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1008977