In Neuron ; h5-index 148.0
Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% of HARs have variants with large opposing effects on chromatin state and 14% on neurodevelopmental enhancer activity. This pattern, consistent with compensatory evolution, was confirmed using massively parallel reporter assays in chimpanzee and human neural progenitor cells. The species-specific enhancer activity of HARs was accurately predicted from the presence and absence of transcription factor footprints in each species. Despite these striking cis effects, activity of a given HAR sequence was nearly identical in human and chimpanzee cells. This suggests that HARs did not evolve to compensate for changes in the trans environment but instead altered their ability to bind factors present in both species. Thus, ML prioritized variants with functional effects on human neurodevelopment and revealed an unexpected reason why HARs may have evolved so rapidly.
Whalen Sean, Inoue Fumitaka, Ryu Hane, Fair Tyler, Markenscoff-Papadimitriou Eirene, Keough Kathleen, Kircher Martin, Martin Beth, Alvarado Beatriz, Elor Orry, Laboy Cintron Dianne, Williams Alex, Hassan Samee Md Abul, Thomas Sean, Krencik Robert, Ullian Erik M, Kriegstein Arnold, Rubenstein John L, Shendure Jay, Pollen Alex A, Ahituv Nadav, Pollard Katherine S
2023-Jan-05
ATAC-seq, ChIP-seq, Hi-C, MPRA, accelerated regions, enhancers, evolution, gene regulation, machine learning, neurodevelopment
