ArticleNeuron2023
Machine learning dissection of human accelerated regions in primate neurodevelopment.
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Article in Neuron, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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62citing papers in PubMed
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Who cites it
62 citing papers in PubMed, 89 citations in OpenAlex.
- Human-specific morphoregulatory signatures in basal radial glia characterise neocortex evolution.Nature communications · 2026Article
- A Human Accelerated Region Drives Opposing Heterochronic Changes in Craniofacial and Limb Development.bioRxiv : the preprint server for biology · 2026Article
- Article
- Positive selection on brain cis-regulatory elements in the human lineage drives changes in gene expression and susceptibility to neuropsychiatric disorders.HGG advances · 2026Article
- A LINE-1 insertion upstream of FOXP2 promotes neuronal differentiation during primate evolution.Genome biology · 2026Article
- In Vitro Massively Parallel Screening of Human Regulatory Elements Involved in Postcranial Skeletal Development for Differential Activity Compared to Chimpanzee.Genome biology and evolution · 2026Article
- Genomic approaches for understanding the evolution of the human brain.Nature neuroscience · 2026Review
- Genomic-microbial coevolution in human development: chromosome 2 fusion, and human accelerated regions.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Cross-species prediction reveals chromatin regions with increased accessibility in humans.Science advances · 2026Article
- Species-specific chromatin architecture and neurogenesis mediated by a human enhancer.Cell stem cell · 2026Article
- In silico genome transplants and the cis-regulatory basis of biodiversity.Trends in genetics : TIG · 2026Review
- The evolution of gene regulation in mammalian cerebellum development.Science (New York, N.Y.) · 2026Article
- Structural variations in evolutionary novel genomic regions: new insights into neurodevelopmental disorders by long-read DNA Sequencing.Molecular medicine (Cambridge, Mass.) · 2026Article
- Mapping cis- and trans-regulatory target genes of human-specific deletions.Nature communications · 2025Article
- Comparative genomics sheds light on mammalian and avian gene regulation and phenotypic evolution.Nature communications · 2025Article
- Ultra-fast variant effect prediction using biophysical transcription factor binding models.Nucleic acids research · 2025Article
- An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility.Science advances · 2025Article
- Lineage-specific regulatory evolution: insights from massively parallel reporter assays.Current opinion in genetics & development · 2025Review
- Article
- Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution.Nature communications · 2025Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 5 institutions in 2 countries.
Sean WhalenGladstone Institutes, San Francisco, CA 94158, USA.
Fumitaka InoueDepartment 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.
Hane RyuDepartment 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.
Tyler FairEli 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.
Eirene Markenscoff-PapadimitriouDepartment of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
Kathleen KeoughGladstone Institutes, San Francisco, CA 94158, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Martin KircherDepartment 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.
Beth MartinDepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Beatriz AlvaradoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
Orry ElorDepartment 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.
Dianne Laboy CintronDepartment 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.
Alex WilliamsGladstone Institutes, San Francisco, CA 94158, USA.
Md Abul Hassan SameeGladstone Institutes, San Francisco, CA 94158, USA.
Sean ThomasGladstone Institutes, San Francisco, CA 94158, USA.
Robert KrencikDepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA.
Erik M UllianDepartments 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.
Arnold KriegsteinEli 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.
John L RubensteinDepartment of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
Jay ShendureDepartment 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.
Alex A PollenInstitute 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.
Nadav AhituvDepartment 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.
Katherine S PollardGladstone 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.
University of California, San Francisco · USGladstone Institutes · USUniversity of Washington · USHouston Methodist · USHoward Hughes Medical Institute · US
Funding
Massively parallel characterization of variants and elements impacting transcriptional regulation in dynamic cellular systemsUM1HG011966 · NHGRI · UNIVERSITY OF WASHINGTON · PI Nadav Ahituv, Jay Ashok Shendure · 2021 to 2026
$9.7MDevelopment and Expansion of the Human Cerebral CortexR35NS097305 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KRIEGSTEIN, ARNOLD · 2017 to 2024
$8.5MPREDOCTORAL TRAINING IN DEVELOPMENTAL BIOLOGYT32HD007470 · NICHD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Todd Nystul · 1994 to 2026
$7.7MMassively parallel reporter assays and genome editing of ENCODE predicted regulatory elementsUM1HG009408 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, SHENDURE, JAY ASHOK · 2017 to 2021
$7.6MGenetic Studies of Cortex Structure and DevelopmentR01NS099099 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI RUBENSTEIN, JOHN L. R. · 2016 to 2025
$6.4MRestorative practice in repairing harm and promoting safe and inclusive practices in the laboratory.T32GM136547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Adrian Erlebacher, Anita Sil · 2020 to 2026
$4.5MMassively parallel dissection of psychiatric regulatory networksR01MH109907 · NIMH · J. DAVID GLADSTONE INSTITUTES · PI AHITUV, NADAV, POLLARD, KATHERINE S. · 2016 to 2020
$3.4MMassively parallel characterization of psychiatric disease associated regulatory elements in defined cell typesU01MH116438 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, POLLARD, KATHERINE S. · 2018 to 2021
$2.7MResolving single-cell brain regulatory elements with bulk data supervised modelsR01MH123178 · NIMH · J. DAVID GLADSTONE INSTITUTES · PI POLLARD, KATHERINE S. · 2020 to 2023
$2.4MEstablishing A Stem Cell Biology Platform for Decoding the Genetic Basis of Human Brain SpecializationsDP2MH122400 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI POLLEN, ALEXANDER A · 2019 to 2019
$2.4MMassively parallel characterization of psychiatric disease associated regulatory elements in defined cell typesR01MH116438 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, POLLARD, KATHERINE S. · 2022 to 2022
$668kFunctional Genetics Approaches to Investigate Human EvolutionF31HG011569 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FAIR, TYLER · 2021 to 2023
$114kNHGRI NIH HHS F31 HG011569NHGRI NIH HHS UM1 HG009408NHGRI NIH HHS UM1 HG011966NICHD NIH HHS T32 HD007470NIGMS NIH HHS T32 GM136547NIMH NIH HHS DP2 MH122400NIMH NIH HHS R01 MH109907NIMH NIH HHS R01 MH123178NIMH NIH HHS U01 MH116438NINDS NIH HHS R01 NS099099NINDS NIH HHS R35 NS097305
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.
Indexed as
BrainEnhancer Elements, GeneticPan troglodytesAnimalsChromatinHumansMachine LearningTranscription FactorsChromatinTranscription Factorsaccelerated regionsATAC-seqChIP-seqenhancersevolutiongene regulationHi-Cmachine learningMPRAneurodevelopment
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