The fundamental challenge in the analysis of complex datasets is to quantify and interpret the contribution of multiple sources of variation. Indeed the most pressing questions concern the relationship between these sources of variation. How does cell or tissue type affect the genetic regulation of gene expression, and does it vary by ancestry [1, 2]? What is the relative contribution of experimental stimulus versus regulatory genetics to variation in gene expression [5]? Is technical variability of RNA-seq low enough to study regulatory genetics and disease biology, and what are the major drivers of this technical variability [2, 8, 9]? A rich understanding of complex datasets requires answering these questions with both a genome-wide summary and gene-level resolution.
