@article{b7a108f2b1df46ba9fbfe0a73265b0c4,
title = "Machine learning dissection of human accelerated regions in primate neurodevelopment",
abstract = "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.",
keywords = "ATAC-seq, ChIP-seq, Hi-C, MPRA, accelerated regions, enhancers, evolution, gene regulation, machine learning, neurodevelopment, Chromatin, Humans, Transcription Factors/genetics, Machine Learning, Brain/growth & development, Pan troglodytes/metabolism, Animals, Enhancer Elements, Genetic",
author = "Sean Whalen and Fumitaka Inoue and Hane Ryu and Tyler Fair and Eirene Markenscoff-Papadimitriou and Kathleen Keough and Martin Kircher and Beth Martin and Beatriz Alvarado and Orry Elor and {Laboy Cintron}, Dianne and Alex Williams and {Hassan Samee}, {Md Abul} and Sean Thomas and Robert Krencik and Ullian, {Erik M.} and Arnold Kriegstein and Rubenstein, {John L.} and Jay Shendure and Pollen, {Alex A.} and Nadav Ahituv and Pollard, {Katherine S.}",
note = "Funding Information: This work was funded by the Gladstone Institutes (K.S.P.), Schmidt Futures Foundation (A.A.P), and NIH grants: DP2MH122400-01 (A.A.P.), R35NS097305 (A.K.), FHG011569A (T.F.), R01MH109907 (N.A. and K.S.P.), U01MH116438 (N.A. and K.S.P.), UM1HG009408 (J.S. and N.A.), UM1HG011966 (J.S. and N.A.), and 2R01NS099099 (J.L.R.). K.S.P. is a Chan Zuckerberg Investigator. A.A.P. is a New York Stem Cell Foundation Robertson Investigator and member of the UCSF Kavli Institute for Fundamental Neuroscience. S.W. H.R. F.I. N.A. and K.S.P. conceived and designed the study. S.W. A.W. S.T. and K.S.P. designed the lentiMPRA library. S.W. K.K. M.K. M.A.H.S. and K.S.P. analyzed data and performed modeling. F.I. H.R. T.F. A.A.P. E.M.-P. B.M. B.A. O.E. D.L.C. and R.K. performed experiments. S.W. F.I. H.R. E.M.-P. J.S. A.A.P. N.A. and K.S.P. interpreted results. E.M.U. J.L.R. A.K. J.S. A.A.P. N.A. and K.S.P. supervised and provided funding. S.W. and K.S.P. drafted the manuscript. All authors reviewed and edited the manuscript. A.K. is a cofounder, consultant, and member of the board of Neurona Therapeutic, a company studying the potential therapeutic use of interneuron transplantation. J.L.R. is a cofounder, stockholder, and member of the board of Neurona. N.A. is a cofounder and on the scientific advisory board of Regel Therapeutics and Neomer Diagnostics and receives funding from BioMarin Pharmaceutical Incorporate. K.K. is currently an employee of Fauna Bio. Funding Information: This work was funded by the Gladstone Institutes (K.S.P.), Schmidt Futures Foundation (A.A.P), and NIH grants: DP2MH122400-01 (A.A.P.), R35NS097305 (A.K.), FHG011569A (T.F.), R01MH109907 (N.A. and K.S.P.), U01MH116438 (N.A. and K.S.P.), UM1HG009408 (J.S. and N.A.), UM1HG011966 (J.S. and N.A.), and 2R01NS099099 (J.L.R.). K.S.P. is a Chan Zuckerberg Investigator. A.A.P. is a New York Stem Cell Foundation Robertson Investigator and member of the UCSF Kavli Institute for Fundamental Neuroscience. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2023",
month = mar,
day = "15",
doi = "10.1016/j.neuron.2022.12.026",
language = "English (US)",
volume = "111",
pages = "857--873.e8",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "6",
}