Heritability and genetic basis of protein level variation in an outbred population
- Leopold Parts1,3,
- Yi-Chun Liu1,
- Manu Tekkedil2,
- Lars M Steinmetz2,
- Amy A Caudy1,
- Andrew G Fraser1,
- Charles Boone1,
- Brenda J Andrews1 and
- Adam P Rosebrock1
- ↵* Corresponding author; email: leopold.parts{at}utoronto.ca
Abstract
The genetic basis of heritable traits has been studied for decades Although recent mapping efforts have elucidated genetic determinants of transcript levels, mapping of cellular traits downstream of mRNA levels, such as protein abundance, has lagged. Here, we systematically analyze levels of 4,084 GFP-tagged yeast proteins in the progeny of a cross between a laboratory and a wild strain at single-cell resolution using flow cytometry and high-content microscopy. The genotype of trans variants contributed little to protein level variation between individual cells, but explained over 50% of the variance in the population average protein abundance for half of the GFP-fusions tested. To map trans-acting factors responsible for the heritable expression variation, we performed flow sorting and bulk segregant analysis of twenty-five proteins, finding a median of five protein quantitative trait loci (pQTLs) per GFP-fusion. In our mapping analysis, we find that cis-acting variants predominate; the genotype of a gene and its surrounding region had a large effect on protein level six times more frequently than the rest of the genome combined. We present evidence for both shared and independent genetic control of transcript and protein abundance: over half of the expression QTLs (eQTLs) contribute to changes in protein levels of regulated genes, but several pQTLs do not affect their cognate transcript levels. Allele replacements of genes known to underlie trans eQTL hotspots confirmed correlation of effects on mRNA and protein levels. This study represents the first genome-scale measurement of genetic contribution to protein levels in single cells and populations, identifies over a hundred trans pQTLs, and validates the propagation of effects associated with transcript variation to protein abundance.
- Received December 4, 2013.
- Accepted May 6, 2014.
- Published by Cold Spring Harbor Laboratory Press
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