Allelic expression of deleterious protein-coding variants across human tissues

PLoS Genet. 2014 May 1;10(5):e1004304. doi: 10.1371/journal.pgen.1004304. eCollection 2014 May.

Abstract

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles*
  • Exome
  • Humans
  • Polymerase Chain Reaction
  • Proteins / genetics*

Substances

  • Proteins

Associated data

  • GEO/GSE51769

Grants and funding

This research was conducted with government support under and awarded by DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEG) Fellowship, 32 CFR 168a. SBM is funded by the Edward Mallinckrodt Jr. Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.