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bioRxiv · 10.1101/2023.02.14.528376

Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans

Hansen, T. J.·Fong, S.·Capra, J. A.·Hodges, E.
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Abstract

Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using ATAC-STARR-seq. In addition to thousands of cis changes, we discover an unexpected number (~10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie >50% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence--alone and together with cis changes--to regulatory differences between species.

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Hansen, T. J., Fong, S., Capra, J. A., Hodges, E.. 2023-02-15. Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans. https://doi.org/10.1101/2023.02.14.528376

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