Determinants of transcriptome and proteome variation in human induced pluripotent stem cells

Abstract
Induced pluripotent stem cell (iPSC) technology holds great promise for both basic research and clinical applications. A critical step towards these objectives is to understand gene regulation in pluripotent cells. The Human Induced Pluripotent Stem Cells Initiative (HipSci) has generated, genotyped, and phenotyped iPSC lines from hundreds of genetically diverse donors. These data, which now include RNA-seq data from ~600 lines, and quantitative proteomics data from ~200 lines, provide a unique resource for understanding the drivers of variation across iPSCs. Our analysis revealed coordinated changes at the transcriptome and proteome levels. Many protein changes were not observed at the transcript level, and were driven by coordinated changes in organelles and protein complexes, including many complexes involved in respiratory metabolism. In addition, donor genetics exhibited significant effects on protein abundance. To identify the specific genetic variants underlying this, we tested for expression and protein quantitative trait loci (eQTL, pQTL, respectively). This identified significant cis eQTLs for more than ~45% of expressed transcripts, and significant cis pQTLs for ~10% of quantified proteins (FDR=0.05), with highly consistent effects observed between overlapping eQTLs and pQTLs. Together, our results describe important system-level variability in iPSC gene and protein regulation, and their underlying genetic basis.