Heritability and genetic basis of protein level variation in an outbred population.
The genetic basis of heritable traits has been studied for decades. Although recent mapping efforts have elucidated genetic determinants of transcript levels, mapping of protein abundance has lagged. Here, we analyze levels of 4084 GFP-tagged yeast proteins in the progeny of a cross between a laboratory and a wild strain using flow cytometry and high-content microscopy. The genotype of trans variants contributed little to protein level variation between individual cells but explained >50% of the variance in the population's average protein abundance for half of the GFP fusions tested. To map trans-acting factors responsible, we performed flow sorting and bulk segregant analysis of 25 proteins, finding a median of five protein quantitative trait loci (pQTLs) per GFP fusion. Further, 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: More than 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 the 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 more than a hundred trans pQTLs, and validates the propagation of effects associated with transcript variation to protein abundance.
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, M5S3E1, Canada leopold.parts@utoronto.ca charlie.boone@utoronto.ca brenda.andrews@utoronto.ca adam.rosebrock@utoronto.ca.
Leopold
L
Parts
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada;
Yi-Chun
YC
Liu
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany;
Manu M
MM
Tekkedil
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
Lars M
LM
Steinmetz
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, M5S3E1, Canada.
Amy A
AA
Caudy
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, M5S3E1, Canada.
Andrew G
AG
Fraser
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, M5S3E1, Canada leopold.parts@utoronto.ca charlie.boone@utoronto.ca brenda.andrews@utoronto.ca adam.rosebrock@utoronto.ca.
Charles
C
Boone
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, M5S3E1, Canada leopold.parts@utoronto.ca charlie.boone@utoronto.ca brenda.andrews@utoronto.ca adam.rosebrock@utoronto.ca.
Brenda J
BJ
Andrews
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E1, Canada; leopold.parts@utoronto.ca charlie.boone@utoronto.ca brenda.andrews@utoronto.ca adam.rosebrock@utoronto.ca.
Adam P
AP
Rosebrock
D002874:Chromosome Mapping; D019143:Evolution, Molecular; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D040641:Quantitative Trait Loci; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D012331:RNA, Fungal; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins