Human-chimp hybrid cells reveal gene regulatory evolution underlying skeletal divergence

Despite decades of research, little is known about the gene regulatory differences that shaped human traits. Here, we generated a panel of human-chimpanzee hybrid iPS cells to study divergent gene expression separating these species. The contribution of these cells is two-fold: (1) their chromosomes are exposed to the same cellular environment, and thus, any expression difference between the species can be attributed to genetic differences, rather than environmental or cell culture artifacts, and to cis- rather than trans-regulatory changes. (2) These cells can be stably differentiated, facilitating the study of cell types that are often impossible to obtain from apes. We differentiated the hybrid cells into cranial neural crest cells, the main cells that form the face, and use them to study differential gene regulation that separates humans and chimps. We show that human-chimp expression differences within the hybrid can serve as strong predictors of phenotypic divergence, and that the more extreme the expression change is, the more likely it is to be associated with known human-chimp divergent morphology. Finally, we focus on the most differentially expressed gene, EVC2, which likely became down-regulated along the human lineage, and suggest that its silencing might have played a role in the flattening of the human face, and in shaping our dental and limb morphology through down-regulation of the hedgehog signaling pathway.