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

doi:10.1016/j.neuron.2022.12.026

Machine learning dissection of human accelerated regions in primate neurodevelopment

Neuron. 2023 Mar 15;111(6):857-873.e8. doi: 10.1016/j.neuron.2022.12.026. Epub 2023 Jan 13.

Authors

Sean Whalen¹, Fumitaka Inoue², Hane Ryu³, Tyler Fair⁴, Eirene Markenscoff-Papadimitriou⁵, Kathleen Keough⁶, Martin Kircher⁷, Beth Martin⁸, Beatriz Alvarado⁹, Orry Elor², Dianne Laboy Cintron², Alex Williams¹, Md Abul Hassan Samee¹, Sean Thomas¹, Robert Krencik¹⁰, Erik M Ullian¹¹, Arnold Kriegstein⁴, John L Rubenstein⁵, Jay Shendure¹², Alex A Pollen¹³, Nadav Ahituv¹⁴, Katherine S Pollard¹⁵

Affiliations

¹ Gladstone Institutes, San Francisco, CA 94158, USA.
² 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 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 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 Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
⁶ Gladstone Institutes, San Francisco, CA 94158, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁷ 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 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁹ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ 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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain* / growth & development
Chromatin
Enhancer Elements, Genetic*
Humans
Machine Learning
Pan troglodytes* / metabolism
Transcription Factors / genetics

Substances

Chromatin
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding