Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk.

Autor:	Shin T; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Song JHT; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Kosicki M; Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Kenny C; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Beck SG; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Kelley L; Division of Genetics and Genomics, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School; Allen Discovery Center for Human Brain Evolution, Boston, MA, 02115, USA., Qian X; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Bonacina J; Division of Genetics and Genomics, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School; Allen Discovery Center for Human Brain Evolution, Boston, MA, 02115, USA., Papandile F; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Antony I; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Gonzalez D; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Scotellaro J; Division of Genetics and Genomics, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School; Allen Discovery Center for Human Brain Evolution, Boston, MA, 02115, USA., Bushinsky EM; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Andersen RE; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Maury E; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA., Pennacchio LA; Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Doan RN; Division of Genetics and Genomics, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School; Allen Discovery Center for Human Brain Evolution, Boston, MA, 02115, USA., Walsh CA; Division of Genetics and Genomics, Boston Children's Hospital; Departments of Pediatrics and Neurology, Harvard Medical School; Allen Discovery Center for Human Brain Evolution; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 22. Date of Electronic Publication: 2023 Sep 22.
DOI:	10.1101/2023.09.19.23295780
Abstrakt:	Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding 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 >4900 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, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior. Competing Interests: Declaration of Interests The authors declare no competing interests.
Databáze:	MEDLINE
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