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Machine-learning dissection of Human Accelerated Regions in primate neurodevelopment

Sean Whalen, Fumitaka Inoue, Hane Ryu, Tyler Fairr, Eirene Markenscoff-Papadimitriou, Kathleen Keough, View ORCID ProfileMartin Kircher, Beth Martin, Beatriz Alvarado, Orry Elor, Dianne Laboy Cintron, Alex Williams, View ORCID ProfileMd. Abul Hassan Samee, Sean Thomas, Robert Krencik, Erik M. Ullian, Arnold Kriegstein, John L. Rubenstein, Jay Shendure, Alex A. Pollen, Nadav Ahituv, View ORCID ProfileKatherine S. Pollard
doi: https://doi.org/10.1101/256313
Sean Whalen
1Gladstone Institutes, San Francisco, CA 94158, USA
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Fumitaka Inoue
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
4Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
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Hane Ryu
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
5Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA, USA
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Tyler Fairr
7Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
6Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
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Eirene Markenscoff-Papadimitriou
8Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
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Kathleen Keough
1Gladstone Institutes, San Francisco, CA 94158, USA
5Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA, USA
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Martin Kircher
9Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
10Berlin Institute of Health at Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany
11Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck, 23562 Lübeck, Germany
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  • ORCID record for Martin Kircher
Beth Martin
9Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
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Beatriz Alvarado
6Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
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Orry Elor
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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Dianne Laboy Cintron
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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Alex Williams
1Gladstone Institutes, San Francisco, CA 94158, USA
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Md. Abul Hassan Samee
1Gladstone Institutes, San Francisco, CA 94158, USA
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  • ORCID record for Md. Abul Hassan Samee
Sean Thomas
1Gladstone Institutes, San Francisco, CA 94158, USA
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Robert Krencik
12Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX
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Erik M. Ullian
13Departments of Ophthalmology and Physiology, University of California San Francisco, San Francisco, CA, USA
14Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA
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Arnold Kriegstein
6Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
7Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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John L. Rubenstein
8Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
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Jay Shendure
9Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
15Howard Hughes Medical Institute, Seattle, Washington 98195, USA
16Brotman Baty Institute for Precision Medicine, Seattle, Washington 98195, USA
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Alex A. Pollen
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
6Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
7Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Nadav Ahituv
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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  • For correspondence: katherine.pollard@gladstone.ucsf.edu nadav.ahituv@ucsf.edu
Katherine S. Pollard
1Gladstone Institutes, San Francisco, CA 94158, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
17Department of Epidemiology and Biostatistics and Institute for Computational Health Sciences, University of California San Francisco, San Francisco, CA, USA
18Chan-Zuckerberg Biohub, San Francisco, CA, USA
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  • ORCID record for Katherine S. Pollard
  • For correspondence: katherine.pollard@gladstone.ucsf.edu nadav.ahituv@ucsf.edu
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Abstract

Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 Human Accelerated Regions (HARs), some of the fastest evolving regions of the human genome. We predicted that 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 human and chimpanzee neural progenitor cells. The species-specific enhancer activity of assayed 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. These findings suggest 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Computational analyses were extended to a larger set of 2,645 human accelerated regions. Other changes included addition of statistical tests and reorganization of Figures 4-7.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 28, 2022.
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Machine-learning dissection of Human Accelerated Regions in primate neurodevelopment
Sean Whalen, Fumitaka Inoue, Hane Ryu, Tyler Fairr, 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
bioRxiv 256313; doi: https://doi.org/10.1101/256313
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Machine-learning dissection of Human Accelerated Regions in primate neurodevelopment
Sean Whalen, Fumitaka Inoue, Hane Ryu, Tyler Fairr, 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
bioRxiv 256313; doi: https://doi.org/10.1101/256313

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