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

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 an...

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Published in:Genome research 2015-11, Vol.25 (11), p.1610-1621
Main Authors: Cenik, Can, Cenik, Elif Sarinay, Byeon, Gun W, Grubert, Fabian, Candille, Sophie I, Spacek, Damek, Alsallakh, Bilal, Tilgner, Hagen, Araya, Carlos L, Tang, Hua, Ricci, Emiliano, Snyder, Michael P
Format: Article
Language:English
Subjects:
Chromatin - genetics
Chromatin - metabolism
Gene Expression Profiling
Gene Expression Regulation
Humans
Polymorphism, Single Nucleotide
Protein Biosynthesis
Proteomics
Quantitative Trait Loci
Ribosomes - genetics
Ribosomes - metabolism
RNA - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sequence Alignment
Sequence Analysis, RNA
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Summary: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.
ISSN:1088-9051
1549-5469
DOI:10.1101/gr.193342.115