Human-chimpanzee tetraploid system defines mechanisms of species-specific neural gene regulation

A major challenge in human evolutionary biology is to pinpoint genetic differences that underlie human-specific traits, such as increased neuron number and differences in cognitive behaviors. We used human-chimpanzee tetraploid cells to distinguish gene expression changes due tocis-acting sequence variants that change local gene regulation, fromtransexpression changes due to species differences in the cellular environment. In neural progenitor cells, examination of bothcisandtranschanges — combined with CRISPR inhibition and transcription factor motif analyses — identifiedcis-acting, species-specific gene regulatory changes, including toTNIK, FOSL2, andMAZ, with widespreadtranseffects on neurogenesis-related gene programs. In excitatory neurons, we identifiedPOU3F2as a keycis-regulated gene withtranseffects on synaptic gene expression and neuronal firing. This study identifiescis-acting genomic changes that cause cascadingtransgene regulatory effects to contribute to human neural specializations, and provides a general framework for discovering genetic differences underlying human traits.