The Identification and Impact of 3'UTR Regulatory Variants on Phenotype and Disease.

Abstract

Genetic variation is a major cause of disease susceptibility, and sequence variants can change both protein function and stoichiometry. Though posttranscriptional regulation is a major component of mammalian gene expression control, single-nucleotide polymorphisms (SNPs) within 3' untranslated regions (UTRs) remain an underexplored source of variation impacting human health. Nevertheless, seminal studies have found that functionally relevant SNPs, including expression quantitative trait loci (eQTLs), are enriched in 3'UTRs. These discoveries highlight the importance of SNPs within 3'UTRs. Here, we provide an overview of techniques used to prioritize and validate 3'UTR SNPs. Computational methods, such as association assays and scoring frameworks, allow for SNP prioritization, and recent experimental methods have enabled the validation of many SNPs in parallel. We discuss examples of 3'UTR SNPs that are relevant to human health and development, as well as how the patterns and prevalence of 3'UTR SNPs can be used to identify selection on the cis-regulatory sites and trans-factors that underlie posttranscriptional regulation.