한빛사논문
- 조회207
Il Bin Kim 1,2,10, Myeong-Heui Kim 2,10, Saehoon Jung 2, Woo Kyeong Kim 2, Junehawk Lee 3, Young Seok Ju 2, Maree J. Webster 4, Sanghyeon Kim 4, Ja Hye Kim 5, Hyun Jung Kim 6, Junho Kim 7,*, Sangwoo Kim 8,* and Jeong Ho Lee 2,9,*
1Department of Psychiatry, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul 06135, Republic of Korea.
2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
3Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon 34141, Republic of Korea.
4Stanley Medical Research Institute, Laboratory of Brain Research, 9800 Medical Center Drive, Suite C-050, Rockville, MD 20850, USA.
5Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
6Department of Anatomy, Korea University College of Medicine, Seoul 02841, Republic of Korea.
7Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
8Department of Biomedical Systems Informatics and Brain Korea 21 PLUS for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
9SoVarGen, SoVarGen, Inc., Daejeon 34141, Republic of Korea.
10These authors contributed equally: Il Bin Kim, Myeong-Heui Kim.
*Corresponding authors: correspondence to Junho Kim, Sangwoo Kim or Jeong Ho Lee
Abstract
Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12–14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-01)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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