Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing

Sci Rep. 2016 Sep 12;6:32406. doi: 10.1038/srep32406.

Abstract

Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA- and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA-processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing-alternative splice sites, introns, and cleavage sites-which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Alternative Splicing*
  • Base Sequence
  • Exons
  • Gene Frequency
  • Genetic Variation*
  • Genome, Human*
  • Humans
  • Introns
  • Polyadenylation
  • RNA Editing*
  • RNA Splice Sites*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Sequence Analysis, RNA

Substances

  • RNA Splice Sites
  • RNA, Messenger