ArticleNeuron2021
Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions.
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Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers, 1 of them a synthesis that pooled it.
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113citing papers in PubMed, 1 pooled it
12.3field-weighted citation impact, top 1% of its field
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Who cites it
113 citing papers in PubMed, 1 synthesis or guideline pooled it, 192 citations in OpenAlex.
- A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge.International journal of molecular sciences · 2023Pooled it
- Human-specific morphoregulatory signatures in basal radial glia characterise neocortex evolution.Nature communications · 2026Article
- Phosphoproteomic dysregulation promotes tumor proliferation in Cushing's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Regulatory Evolution and the Genetic Basis of Human Brain Expansion.Journal of molecular evolution · 2026Review
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- Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment.PLoS computational biology · 2026Article
- Positive selection on brain cis-regulatory elements in the human lineage drives changes in gene expression and susceptibility to neuropsychiatric disorders.HGG advances · 2026Article
- Charting the human-specific properties of gene expression networks in the infant prefrontal cortex.Science advances · 2026Article
- Genomic approaches for understanding the evolution of the human brain.Nature neuroscience · 2026Review
- 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
- Adaptive loss of function accelerated the evolution of ancient and modern human cognition.bioRxiv : the preprint server for biology · 2026Article
- Cross-species prediction reveals chromatin regions with increased accessibility in humans.Science advances · 2026Article
- Molecular dynamics of Brodmann Area 22 in development and autism.bioRxiv : the preprint server for biology · 2026Article
- Species-specific chromatin architecture and neurogenesis mediated by a human enhancer.Cell stem cell · 2026Article
- So Fragile, So Human: Noncoding DNA Regions Orchestrating Gene Expression Involved in Neurodevelopmental Disorders and in Human Brain Evolution.International journal of molecular sciences · 2026Review
- Phylogenetic Analysis of NEAT1 and MALAT1 Long Non-Coding RNAs Highlights Structure-Function Relationships in Paraspeckle Biology.Molecular biology and evolution · 2026Article
- Trans-ancestry genome-wide analyses of bipolar disorder in East Asian and European populations improve genetic discovery.Nature neuroscience · 2026Article
- Transcriptomic divergence of network hubs in the prenatal human brain.Communications biology · 2025Article
- Large-scale discovery of neural enhancers for cis-regulation therapies.bioRxiv : the preprint server for biology · 2025Article
- Neocortical neurogenesis: a proneural gene perspective.The FEBS journal · 2025Review
53 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
25 authors at 8 institutions in 1 country.
Kelly M GirskisDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
Andrew B StergachisDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
Ellen M DeGennaroDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ryan N DoanDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Xuyu QianDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Matthew B JohnsonDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Peter P WangDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Gabrielle M SejourneDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
M Aurel NagyAllen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Elizabeth A PollinaAllen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
André M M SousaDepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Taehwan ShinDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston MA, USA.
Connor J KennyDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Julia L ScotellaroDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Brian M DeboDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Dilenny M GonzalezDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Lariza M RentoDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Rebecca C YehDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Janet H T SongDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Marc BeaudinDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jean FanDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Peter V KharchenkoDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
Nenad SestanDepartment of Neurobiology, Harvard Medical School, Boston, MA, USA.
Michael E GreenbergAllen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Christopher A WalshDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
Harvard University · USDana-Farber/Boston Children's Cancer and Blood Disorders Center · USBoston Children's Hospital · USBroad Institute · USUniversity of Washington Medical Center · USHarvard Stem Cell Institute · USHoward Hughes Medical Institute · USJohns Hopkins University · US
Funding
Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MPHD TRAINING IN NEUROSCIENCET32MH020017 · NIMH · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JOHN ASSAD · 1997 to 2026
$15.8MCell Identity Determination In Human Brain: Somatic Mutation and Cell LineageR01NS032457 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI Alice Eunjung Lee, Christopher A. Walsh · 1995 to 2026
$12.7MTRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0MGenetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Hisashi Umemori · 2021 to 2026
$9.4M Functional Genomics of Human Brain DevelopmentP50MH106934 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2014 to 2019
$7.9M1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and DisordersU01MH116488 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2018 to 2022
$6.5MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI SAHIN, MUSTAFA · 2016 to 2020
$5.2MOrchestra: A high performance biomedical supercomputing collaborativeS10RR028832 · NCRR · HARVARD MEDICAL SCHOOL · PI DANUSER, GAUDENZ · 2010 to 2010
$3.7MHeterogeneity of Forebrain Neural PrecursorsR01NS095654 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI HAYDAR, TARIK F, SESTAN, NENAD · 2015 to 2019
$3.4MMechanisms Underlying Neuronal Enhancer Specification During Postnatal CNS DevelopmentR01NS115965 · NINDS · HARVARD MEDICAL SCHOOL · PI GREENBERG, MICHAEL ELDON · 2020 to 2024
$3.2MInvestigating the contribution of non-coding genetic variation to rare disordersDP5OD029630 · OD · UNIVERSITY OF WASHINGTON · PI STERGACHIS, ANDREW BEN · 2020 to 2024
$1.9MHoward Hughes Medical InstituteNCI NIH HHS K00 CA222750NCRR NIH HHS S10 RR028832NICHD NIH HHS P50 HD105351NICHD NIH HHS U54 HD090255NIGMS NIH HHS T32 GM007748NIGMS NIH HHS T32 GM007753NIH HHS DP5 OD029630NIMH NIH HHS P50 MH106934NIMH NIH HHS T32 MH020017NIMH NIH HHS U01 MH116488NINDS NIH HHS R01 NS032457NINDS NIH HHS R01 NS095654NINDS NIH HHS R01 NS115965
Abstract
Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.
Indexed as
AnimalsBiological EvolutionBrainEpigenomicsEvolution, MolecularFerretsGene Expression Regulation, DevelopmentalGene Regulatory NetworksHumansMacacaMicePan troglodytescerebral cortexenhancersevolutionHARshuman accelerated regionsneurodevelopment
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