title: Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans.
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.
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Can
authors: C
authors: Cenik
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Elif Sarinay
authors: ES
authors: Cenik
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Gun W
authors: GW
authors: Byeon
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Fabian
authors: F
authors: Grubert
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Sophie I
authors: SI
authors: Candille
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Damek
authors: D
authors: Spacek
authors: Institute of Software Technology and Interactive Systems, Vienna University of Technology, A-140 Vienna, Austria;
authors: Bilal
authors: B
authors: Alsallakh
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Hagen
authors: H
authors: Tilgner
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Carlos L
authors: CL
authors: Araya
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Hua
authors: H
authors: Tang
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; CIRI, International Center for Infectiology Research, Eukaryotic and Viral Translation Team, Université de Lyon, INSERM U1111, Lyon, 69634, France.
authors: Emiliano
authors: E
authors: Ricci
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors: Michael P
authors: MP
authors: Snyder
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D040901:Proteomics; D040641:Quantitative Trait Loci; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA
chemical_list: D002843:Chromatin; D012333:RNA, Messenger; D012313:RNA