Heritable variation in gene expression provides a critical bridge between differences in genome sequence and the biology of many traits, including common human diseases. However, the sources of most regulatory genetic variation remain unknown. Here, we used transcriptome profiling in 1,012 yeast segregants to map the genetic basis of variation in gene expression with high statistical power. We identified expression quantitative trait loci (eQTL) that together account for over 70% of the total genetic contribution to variation in mRNA levels, allowing us to examine the sources of regulatory variation comprehensively. We found that variation in the expression of a typical gene has a complex genetic architecture involving multiple eQTL. We also detected hundreds of eQTL pairs with significant non-additive interactions in an unbiased genome-wide scan. Although most genes were influenced by a local eQTL located close to the gene, most expression variation arose from distant, trans-acting eQTL located far from their target genes. Nearly all distant eQTL clustered at 102 "hotspot" locations, some of which influenced the expression of thousands of genes. Hotspot regions were enriched for transcription factor genes and altered expression of their target genes though both direct and indirect mechanisms. Many local eQTL had no detectable effects on the expression of other genes in trans. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.
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