The roles of RNA processing in translating genotype to phenotype

• Published in: Nature reviews. Molecular cell biology Vol. 18; no. 2; pp. 102 - 114
• Main Authors: Manning, Kassie S., Cooper, Thomas A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2017; Nature Publishing Group
• Subjects: 631/337/1645; Binding sites; Biochemistry; Cancer Research; Cell Biology; Developmental Biology; Disease; Epigenetic inheritance; Gene Expression Regulation; Genes; Genetic Association Studies; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genetics; Genomes; Genotype & phenotype; Half-Life; Health aspects; Humans; Life Sciences; Localization; Messenger RNA; MicroRNAs; Molecular structure; Mutation; Observations; Polyadenylation; Properties; Proteins; review-article; RNA Precursors - genetics; RNA Processing, Post-Transcriptional; RNA Splicing; RNA Stability; Stem Cells
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm.2016.139

Key Points Gene expression involves a cascade of chromosomal, transcriptional and post-transcriptional events. Genomic variants produce differences between individuals in terms of transcriptional and post-transcriptional events at equal frequency. Common genetic variation between individuals contributes to phenotypic diversity. Single-nucleotide variants can have functional consequences by affecting RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency. Genomic variants affect RNA processing by altering the binding sites of sequence-specific RNA-binding proteins, by disrupting RNA structures required for processing or by introducing RNA structures that prevent RNA processing. Comparisons of genomic and transcriptomic sequences from a large number of individuals from diverse backgrounds will not only identify functional variants that are relevant to human health, but also catalogue the cis -acting elements that are required for basal and regulated RNA processing. Analysis of the effects of genomic variants on post-transcriptional regulation of gene expression is made possible by the recent rapid expansion of high-throughput experimental approaches and associated computational analyses. Genetic variants can produce phenotypic traits through effects on RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency. A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.