Simultaneous mRNA and protein quantification in single cells reveals post-transcriptional effects of genetic variation

DNA variants that influence gene expression shape phenotypic variation. Trans-acting variants affect target genes that can be located anywhere in the genome, and may specifically affect their mRNA or protein levels. However, prior work compared genetic loci mapped in different studies or with limited statistical power. Here, we developed a CRISPR-based system for simultaneous quantification of mRNA and protein of a given gene via dual fluorescent reporters in single, live cells of the yeast Saccharomyces cerevisiae. In large populations of recombinant cells from a cross between two genetically divergent strains, this system revealed 86 trans-acting loci affecting the expression of ten genes. Most loci influenced protein abundance but not mRNA of a given gene. One such locus harbored a premature stop variant in the YAK1 kinase gene, which specifically affected protein or mRNA of dozens of genes. These results demonstrate complex, post-transcriptional genetic effects on gene expression.