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Variation and genetic control of protein abundance in humans

Abstract

Gene expression differs among individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analysed extensively in human populations1,2,3,4,5, our knowledge is limited regarding the differences in human protein abundance and the genetic basis for this difference. Variation in messenger RNA expression is not a perfect surrogate for protein expression because the latter is influenced by an array of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest6,7. Here we used isobaric tag-based quantitative mass spectrometry to determine relative protein levels of 5,953 genes in lymphoblastoid cell lines from 95 diverse individuals genotyped in the HapMap Project8,9. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations and sexes. Levels of specific sets of proteins involved in the same biological process covary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation.

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Figure 1: Overview of workflow and protein association with ethnicity.
Figure 2: Protein covariation network generated by sparse partial correlation estimation.
Figure 3: Loci associated with protein expression levels.

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Acknowledgements

We thank S. Montgomery for providing gene-level RNA sequencing measurements of CEU LCLs. This work was supported by NIH grants to M.S. and H.T.

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Authors and Affiliations

Authors

Contributions

L.W. performed all the experimental work, mass spectrometry-related data analysis and part of the statistical data analysis. S.I.C. performed most of the statistical data analysis. Y.C. performed the protein covariation analysis. D.X. performed the screening of allele-specific peptides. L.J. helped on instrument maintenance. J.L.-P.-T. contributed text and comments to the manuscript. L.W. and S.I.C. wrote the manuscript and participated in detailed discussion of study design and data analysis at all stages of the study. M.S. and H.T. designed and supervised the project.

Corresponding authors

Correspondence to Hua Tang or Michael Snyder.

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Competing interests

The authors declare no competing financial interests.

Additional information

Mass spectrometry raw data and searching results have been deposited in Peptide Atlas and are available at http://www.peptideatlas.org/PASS/PASS00230.

Supplementary information

Supplementary Information

This file contains a Supplementary Guide, which includes a list of the Supplementary Tables, Supplementary Methods, Supplementary References and Supplementary Figures 1-11. (PDF 1366 kb)

Supplementary Data

This zipped file contains Supplementary Tables 1-8 (see the Supplementary Information file for details). (ZIP 7397 kb)

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Wu, L., Candille, S., Choi, Y. et al. Variation and genetic control of protein abundance in humans. Nature 499, 79–82 (2013). https://doi.org/10.1038/nature12223

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