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Neuron
03 15, 2023;111 (6): 857-873.e8.

Machine learning dissection of human accelerated regions in primate neurodevelopment.

Sean Whalen, Fumitaka Inoue, Hane Ryu, Tyler Fair, Eirene Markenscoff-Papadimitriou, Kathleen Keough, Martin Kircher, Beth Martin, Beatriz Alvarado, Orry Elor, Dianne Laboy Cintron, Alex Williams, Md Abul Hassan Samee, Sean Thomas, Robert Krencik, Erik M Ullian, Arnold Kriegstein, John L Rubenstein, Jay Shendure, Alex A Pollen, Nadav Ahituv, Katherine S Pollard
Author Information
  1. Sean Whalen: Gladstone Institutes, San Francisco, CA 94158, USA.
  2. Fumitaka Inoue: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  3. Hane Ryu: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  4. Tyler Fair: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  5. Eirene Markenscoff-Papadimitriou: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
  6. Kathleen Keough: Gladstone Institutes, San Francisco, CA 94158, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  7. Martin Kircher: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck, 23562 Lübeck, Germany.
  8. Beth Martin: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  9. Beatriz Alvarado: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  10. Orry Elor: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  11. Dianne Laboy Cintron: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  12. Alex Williams: Gladstone Institutes, San Francisco, CA 94158, USA.
  13. Md Abul Hassan Samee: Gladstone Institutes, San Francisco, CA 94158, USA.
  14. Sean Thomas: Gladstone Institutes, San Francisco, CA 94158, USA.
  15. Robert Krencik: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA.
  16. Erik M Ullian: Departments of Ophthalmology and Physiology, University of California, San Francisco, San Francisco, CA, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA.
  17. Arnold Kriegstein: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  18. John L Rubenstein: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
  19. Jay Shendure: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
  20. Alex A Pollen: Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  21. Nadav Ahituv: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. Electronic address: nadav.ahituv@ucsf.edu.
  22. Katherine S Pollard: Gladstone Institutes, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics and Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA. Electronic address: katherine.pollard@gladstone.ucsf.edu.
PMID: 36640767 DOI: 10.1016/j.neuron.2022.12.026

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

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Grants

  1. U01 MH116438/NIMH NIH HHS
  2. T32 GM136547/NIGMS NIH HHS
  3. UM1 HG009408/NHGRI NIH HHS
  4. F31 HG011569/NHGRI NIH HHS
  5. R01 MH109907/NIMH NIH HHS
  6. R35 NS097305/NINDS NIH HHS
  7. UM1 HG011966/NHGRI NIH HHS
  8. R01 NS099099/NINDS NIH HHS
  9. R01 MH123178/NIMH NIH HHS
  10. DP2 MH122400/NIMH NIH HHS

MeSH Term

Animals
Humans
Chromatin
Enhancer Elements, Genetic
Machine Learning
Pan troglodytes
Transcription Factors
Brain

Chemicals

Chromatin
Transcription Factors
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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