Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans

  1. Michael P. Snyder1
  1. 1Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
  2. 2Institute of Software Technology and Interactive Systems, Vienna University of Technology, A-140 Vienna, Austria;
  3. 3RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
  4. 4CIRI, International Center for Infectiology Research, Eukaryotic and Viral Translation Team, Université de Lyon, INSERM U1111, Lyon, 69634, France
  1. Corresponding author: mpsnyder{at}stanford.edu

Abstract

Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves the identification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy—many of these differences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation.

Footnotes

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.193342.115.

  • Freely available online through the Genome Research Open Access option.

  • Received April 24, 2015.
  • Accepted August 20, 2015.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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