Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome

Science. 2015 May 8;348(6235):666-9. doi: 10.1126/science.1261877.


Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Silencing
  • Genetic Variation*
  • Genome, Human / genetics*
  • Heterozygote
  • Humans
  • Nonsense Mediated mRNA Decay
  • Phenotype
  • Proteins / genetics*
  • Transcriptome*


  • Proteins

Associated data

  • dbGaP/PHS000424.V3.P1
  • dbGaP/PHS000424.V5.P1
  • dbGaP/PHS000424.V6.P1

Grant support