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

Gene regulatory divergence between species can result from -acting local changes to regulatory element DNA sequences or global -acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying acting changes. We...

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Bibliographic Details
Published inbioRxiv : the preprint server for biology
Main Authors Hansen, Tyler, Fong, Sarah, Capra, John A, Hodges, Emily
Format Journal Article
LanguageEnglish
Published United States 15.02.2023
Subjects
Gene Regulation
DNA Regulatory Elements
Lymphoblastoid Cell Lines
Functional Genomics
Massively Parallel Reporter Assays
Human Evolution
Comparative Genomics
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Summary:Gene regulatory divergence between species can result from -acting local changes to regulatory element DNA sequences or global -acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying acting changes. We present a comprehensive approach to directly identify and divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using ATAC-STARR-seq. In addition to thousands of changes, we discover an unexpected number (~10,000) of changes and show that and elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie >50% of differences and trace how changes can produce cascades of changes. Overall, we find that most divergent elements (67%) experienced changes in both and , revealing a substantial role for divergence-alone and together with changes-to regulatory differences between species.