Cell-type-specific cis-regulatory divergence in gene expression and chromatin accessibility revealed by human-chimpanzee hybrid cells

Abstract

Although gene expression divergence has long been postulated to be the primary driver of human evolution, identifying the genes and genetic variants underlying uniquely human traits has proven to be quite challenging. Theory suggests that cell type-specific cis-regulatory variants may fuel evolutionary adaptation due to the specificity of their effects. These variants can precisely tune the expression of a single gene in a single cell type, avoiding the potentially deleterious consequences of trans-acting changes and non-cell type-specific changes that can impact many genes and cell types, respectively. It has recently become possible to quantify human-specific cis-acting regulatory divergence by measuring allele-specific expression in human-chimpanzee hybrid cells—the product of fusing induced pluripotent stem (iPS) cells of each species in vitro. However, these cis-regulatory changes have only been explored in a limited number of tissues and cell types. Here, we quantify human-chimpanzee cis-regulatory divergence in gene expression and chromatin accessibility across six cell types, enabling the identification of highly cell type-specific cis-regulatory changes. We find that cell type-specific genes and regulatory elements evolve faster than those shared across cell types, suggesting an important role for genes with cell type-specific expression in human evolution. Furthermore, we identify several instances of lineage-specific natural selection that may have played key roles in specific cell types, such as coordinated changes in the cis-regulation of dozens of genes involved in neuronal firing in motor neurons. Finally, using novel metrics and a machine learning model, we identify genetic variants that likely alter chromatin accessibility and transcription factor binding, leading to neuron-specific changes in the expression of the neurodevelopmentally important genes FABP7 and GAD1. Overall, our results demonstrate that integrative analysis of cis-regulatory divergence in chromatin accessibility and gene expression across cell types is a promising approach to identify the specific genes and genetic variants that make us human.

Stem cell transcriptional profiles from mouse subspecies revealcis-regulatory evolution at translation genes

“…In the current work, we have detected sequence signatures of selection between mouse subspecies in a cohort of translation genes that also exhibits directional, polygenic cis-and trans-acting regulatory variation in stem cells. Against a backdrop of other case studies focused on cis-regulatory change as detected in transcriptomes (Fraser et al, 2010(Fraser et al, , 2011Bullard et al, 2010;Martin et al, 2012;York et al, 2018;Agoglia et al, 2021;Gokhman et al, 2021;Mack et al, 2023;Wang et al, 2024), our results represent a proof of concept for sequence-based validation of this approach in mammals.…”

“…Against a backdrop of other case studies focused on cis-regulatory change as detected in transcriptomes (Bullard et al 2010;Fraser et al 2010;Fraser et al 2011;Martin et al 2012;York et al 2018;Agoglia et al 2021;Gokhman et al 2021;Mack et al 2023;Wang et al 2024), our results represent a proof of concept for sequence-based validation of this approach in mammals.…”