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Genetic basis of proteome variation in yeast

Abstract

Proper regulation of protein levels is essential for health, and abnormal levels of proteins are hallmarks of many diseases. A number of studies have recently shown that messenger RNA levels vary among individuals of a species and that genetic linkage analysis can be used to identify quantitative trait loci that influence these levels. By contrast, little is known about the genetic basis of variation in protein levels in genetically diverse populations, in large part because techniques for large-scale measurements of protein abundance lag far behind those for measuring transcript abundance. Here we describe a label-free, mass spectrometry–based approach to measuring protein levels in total unfractionated cellular proteins, and we apply this approach to elucidate the genetic basis of variation in protein abundance in a cross between two diverse strains of yeast. Loci that influenced protein abundance differed from those that influenced transcript levels, emphasizing the importance of direct analysis of the proteome.

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Figure 1: Schematic of method for alignment of MS matrices.
Figure 2: Protein quantifications by western blotting and by MS measurements are comparable.
Figure 3: Peptide levels in parents and segregants.
Figure 4: Linkage hot spots plotted against genome location.

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Acknowledgements

We thank J. Akey, R. Brem, A. de la Cruz, D. Roberts, J. Ronald and E. Smith for helpful discussions; J. Kim, S. Ryu and G. Taylor for technical assistance; and S. Ryu and E. Smith for sharing unpublished results. This work was supported by the Howard Hughes Medical Institute, by National Center for Research Resources grant 1S10RR17262-01 for purchase of the LTQ-FT (to D.R.G.), by National Institute of Allergy and Infectious Disease grant 1U54 AI57141-01 for Mass Spectrometry Core for the WWAMI Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (to D.R.G.), by National Institute of Environmental Health Science (NIEHS) grant P30ES07033 for the University of Washington NIEHS-sponsored Center for Ecogenetics and Environmental Health (to D.R.G.), by National Cancer Institute grant CA015704 (to A.B.), by National Institute of Mental Health grant R37 MH059520 and a James S. McDonnell Foundation Centennial Fellowship (to L.K.) and by Center grant P50GM071508 from the National Institute of General Medical Science to the Lewis-Sigler Institute.

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Correspondence to Dragan Radulovic or Leonid Kruglyak.

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Supplementary Methods, Supplementary Note, Supplementary Figs. 1–3 and Supplementary Table 1 (PDF 1858 kb)

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Foss, E., Radulovic, D., Shaffer, S. et al. Genetic basis of proteome variation in yeast. Nat Genet 39, 1369–1375 (2007). https://doi.org/10.1038/ng.2007.22

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