Disentangling cell-intrinsic and extrinsic factors underlying gene expression evolution
Chimeras have played a foundational role in biology, for example by enabling the classification of developmental processes into those driven intrinsically by individual cells versus those driven extrinsically by their extracellular environment. Here, we extend this framework to decompose evolutionary divergence in gene expression and other quantitative traits into cell-intrinsic, extrinsic, and intrinsic-extrinsic interaction components. Applying this framework to reciprocal rat-mouse chimeras, we found that the majority of gene expression divergence is attributable to cell-intrinsic factors, though extrinsic factors also play an integral role. For example, a rat-like extracellular environment extrinsically up-regulates the expression of a key transcriptional regulator of the endoplasmic reticulum (ER) stress response in some but not all cell types, which in turn strongly predicts extrinsic up-regulation of its target genes and of the ER stress response pathway as a whole. This effect