Accounting for cis-regulatory constraint prioritizes genes likely to affect species-specific traits

Abstract

Measuring differences in allele specific gene expression in hybrids between two different species is a powerful way to detect cis-regulatory changes underlying adaptation. However, these studies frequently identify thousands of differentially expressed genes. This makes it difficult to differentiate candidate genes most likely to explain interspecies phenotypic differences from genes whose expression levels diverge with little evolutionary constraint. Here we outline a simple strategy that leverages population-scale allele-specific RNA-seq data to identify genes that have constrained cis-regulation within species yet show divergence between species. By applying this strategy to data from human/chimpanzee hybrid cortical spheroids we identify signatures of lineage-specific selection on the expression of genes related to cellular proliferation, speech, glucose metabolism, and glycan degradation. In addition, we highlight human-derived differences in the expression of CUX1 and EDNRB that may contribute to differences in neural connectivity and brain size between humans and other primates.

Embryoid bodies facilitate comparative analysis of gene expression in humans and chimpanzees across dozens of cell types

“…Turning our attention to regulatory mechanisms, the use of fused cell lines allowed us to assess the relative contribution of cis and trans changes to regulatory evolution – an approach that has not been feasible in primates until recently (Agoglia et al, 2021; Gokhman et al, 2021; Starr et al, 2022). We found that cis changes are common and can impact any number of cell types, as expected given the potential for spatial and temporal specificity of cis elements.…”

Evolution and dysfunction of human cognitive and social traits: A transcriptional regulation perspective

“…Finally, using allele-specific expression data from human-chimpanzee hybrid cortical spheroids, Starr et al (2022) recently found that expression of CUX1 from the human allele is lower than expression from the chimpanzee allele. These results suggest that reduced TR gene expression has played a role in human brain evolution.…”

“…Since in hybrids both alleles experience the same environment, including trans-acting regulators, this approach is particularly well-suited for identifying cis-regulatory changes between species. Recently, this method was used to detect reduced CUX1 expression in humans (Starr et al, 2022), and we expect future studies using interspecies hybrids to reveal further examples of human-specific TR gene downregulation.…”

“…Maricic et al ( 2013 ) found a regulatory change in FOXP2 specific to modern humans that diminishes binding of the TF POU3F2, thus driving reduced reporter gene expression compared with the ancestral allele. Finally, using allele-specific expression data from human–chimpanzee hybrid cortical spheroids, Starr et al ( 2022 ) recently found that expression of CUX1 from the human allele is lower than expression from the chimpanzee allele. These results suggest that reduced TR gene expression has played a role in human brain evolution.…”