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Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.
Shin, Taehwan; Song, Janet H T; Kosicki, Michael; Kenny, Connor; Beck, Samantha G; Kelley, Lily; Antony, Irene; Qian, Xuyu; Bonacina, Julieta; Papandile, Frances; Gonzalez, Dilenny; Scotellaro, Julia; Bushinsky, Evan M; Andersen, Rebecca E; Maury, Eduardo; Pennacchio, Len A; Doan, Ryan N; Walsh, Christopher A.
Affiliation
  • Shin T; Division 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, U
  • Song JHT; Division 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, U
  • Kosicki M; Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Kenny C; Division 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, U
  • Beck SG; Division 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, U
  • Kelley L; Division 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.
  • Antony I; Division 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, U
  • Qian X; Division 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, U
  • Bonacina J; Division 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.
  • Papandile F; Division 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, U
  • Gonzalez D; Division 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, U
  • Scotellaro J; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • Bushinsky EM; Division 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, U
  • Andersen RE; Division 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, U
  • Maury E; Division 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, U
  • Pennacchio LA; Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Doan RN; Division 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.
  • Walsh CA; Division 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, U
Cell Genom ; 4(8): 100609, 2024 Aug 14.
Article in En | MEDLINE | ID: mdl-39019033
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autism Spectrum Disorder Limits: Female / Humans / Male Language: En Journal: Cell Genom / Cell genomics Year: 2024 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autism Spectrum Disorder Limits: Female / Humans / Male Language: En Journal: Cell Genom / Cell genomics Year: 2024 Document type: Article Country of publication: