ArticleCell genomics2024
Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.
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Article in Cell genomics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29citing papers in PubMed
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29 citing papers in PubMed.
- Article
- Decoding common and rare noncoding variant effects across cellular and developmental contexts.Nature genetics · 2026Article
- Article
- Genomic approaches for understanding the evolution of the human brain.Nature neuroscience · 2026Review
- Species-specific chromatin architecture and neurogenesis mediated by a human enhancer.Cell stem cell · 2026Article
- The inactive X chromosome as a female protector in autism and beyond.Nature genetics · 2026Review
- Inference of Autism Risk Genes Through Comparative Sociogenomics and Molecular Network Analysis.Genes · 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
- Multi-omics Differential Inference for Functional Interpretation (MoDIFI): A Statistical Framework to Prioritize Cell Lines for Neurodevelopmental Variants.bioRxiv : the preprint server for biology · 2026Article
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- Transcriptomic Convergence and the Female Protective Effect in Autism.bioRxiv : the preprint server for biology · 2025Article
- Fascination with RNA Editing: In the Lights of Evolution and Biology.Journal of molecular evolution · 2025Review
- Individuals with intellectual disability have an increased burden ofmedRxiv : the preprint server for health sciences · 2025Article
- The inactive X chromosome as a female protector in autism and beyond.Research square · 2025Article
- Sex differences in the developing human cortex intersect with genetic risk of neurodevelopmental disorders.bioRxiv : the preprint server for biology · 2025Article
- A General Principle of Neuronal Evolution Reveals a Human-Accelerated Neuron Type Potentially Underlying the High Prevalence of Autism in Humans.Molecular biology and evolution · 2025Article
- Advancing precision diagnosis in autism: Insights from large-scale genomic studies.Molecules and cells · 2025Review
- Article
- Article
- Review
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Authors and funding
18 authors.
Taehwan ShinDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Janet H T SongDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Michael KosickiEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Connor KennyDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Samantha G BeckDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Lily KelleyDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA.
Irene AntonyDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Xuyu QianDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Julieta BonacinaDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA.
Frances PapandileDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Dilenny GonzalezDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Julia ScotellaroDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Evan M BushinskyDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Rebecca E AndersenDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Eduardo MauryDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Len A PennacchioEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Ryan N DoanDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA. Electronic address: ryan.doan@childrens.harvard.edu.
Christopher A WalshDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Allen Discovery Center for Human Brain Evolution, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
Funding
Generation of an In Vivo Human Genome Transcriptional Enhancer DatasetR01HG003988 · NHGRI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio · 2006 to 2026
$24.1MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MTRAINING 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
$9.4MEvaluating the Impact of Mutations in Distant-Acting Enhancers in Structural Birth DefectsR01HD114353 · NICHD · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio, Axel Visel · 2023 to 2026
$3.3MGenomic approaches to understand human neural specializationsK99MH136290 · NIMH · BOSTON CHILDREN'S HOSPITAL · PI SONG, JANET · 2024 to 2025
$180kNHGRI NIH HHS R01 HG003988NICHD NIH HHS P50 HD105351NICHD NIH HHS R01 HD114353NIGMS NIH HHS T32 GM007748NIGMS NIH HHS T32 GM144273NIMH NIH HHS K99 MH136290Wellcome Trust
Abstract
Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.
Indexed as
Autism Spectrum DisorderEnhancer Elements, GeneticEvolution, MolecularFemaleGenetic Predisposition to DiseaseHumansMaleautism spectrum disordercaMPRAconsanguineous familiesconserved neural enhancershuman accelerated regionsIL1RAPL1noncoding regionsOTX1SIM1VISTA enhancers
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