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Human gene regulatory evolution is driven by divergence in cis and trans

ABSTRACT: Gene regulation can evolve either by cis-acting local changes to regulatory element DNA sequences or by global changes to the trans-acting regulatory environment; however, the modes favored during recent human evolution are unknown. To date, studies investigating gene regulatory divergence between closely-related species have produced limited estimates on the relative contributions of cis and trans effects on DNA regulatory element activities at a global-scale. By leveraging a comparative ATAC-STARR-seq framework, we identified 10,779 regulatory regions with divergent activity in cis and 10,608 regulatory regions with divergent activity in trans between human and rhesus macaque lymphoblastoid cell lines (LCLs). This revealed substantially more trans effects than predicted and indicates trans-regulatory mechanisms play a larger role in human evolution than previously expected. We also discover that most species-specific regulatory elements (67%) diverge in both cis and trans, suggesting these two mechanisms jointly drive divergent regulatory activity in a single sequence.

ORGANISM(S): Homo sapiens Macaca mulatta

PROVIDER: GSE216917 | GEO | 2023/12/22

REPOSITORIES: GEO

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Project description:Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects on gene expression are due to nearby genetic variants, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. However, as previous studies have mostly assessed the impacts of cis and trans effects at the gene level, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements, including enhancers as well as promoters of both protein-coding and long non-coding RNA genes. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous gene-based studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression between species—or compensatory cis-trans effects—we find that cis-trans compensation is uncommon within individual regulatory elements. Moreover, regulatory elements that do show compensatory cis-trans effects are often less redundant than regulatory elements lacking compensatory cis-trans effects. Thus, our results are consistent with a model wherein compensatory cis-trans effects occur more often through crosstalk between multiple redundant regulatory elements than within a single individual regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.

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Human gene regulatory evolution is driven by divergence in cis and trans

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