We map protein level QTLs in yeast by sorting tens of thousands of yeast meiotic progeny based on fluorescence, and bulk genotyping the populations. The deposited sequence data come from the sorted populations.

The genetic basis of macroscopic heritable traits has been studied for decades. However, mapping the cellular traits that mediate the genotype signal beyond transcript abundance has been challenging due to a lack of appropriate assays. Here, we systematically analyze levels of 4,084 GFP-tagged yeast proteins in large clonal and segregating populations using flow cytometry and an automated imaging pipeline. We find that the genotype of trans variants contributed little to protein level variation in single cells, but explained over 50% of the variance in the population average protein abundance for half of the GFP-fusions tested. Genotype of the gene and its surrounding region had a large effect on protein level six times more frequently than the rest of the genome combined. We mapped regions responsible for the heritable signal for twenty-five proteins, and found a median of five protein quantitative trait loci (pQTLs) per GFP-fusion. While transcript and protein abundance changes were largely independent, and several pQTLs did not affect transcript levels, over half of the expression QTLs (eQTLs) contributed to their protein level as well. We performed allele replacements of genes known to underlie trans eQTL hotspots, and confirmed that their genotype effects on mRNA and protein levels were correlated in magnitude. Our study represents the first genome-scale measurement of genetic contribution to protein abundance in single cells and populations, identifies over a hundred trans pQTLs, and validates the propagation of effects associated with transcript variation to protein levels.