Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes
2
조회
0
다운로드
0
인용
0
참고문헌
초록
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.
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.
참고문헌 (99)
- De Rubeis, S., "Genetics and genomics of autism spectrum dis order : embracing complexity", Hum. Mol. Genet, 24, pp.R24~R31 (2015)
- Choi, L., "Genetic architecture of autism spectrum disorder: Lessons from large-scale genomic studies", Neurosci. Biobehav. Rev, 128, pp.244~257 (2021)[DOI]
- Kim, I. B., "Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder", Mol. Psychiatry, 27, pp.4680~4694 (2022)[DOI]
- Ronald, A., "Genetic heterogeneity between the three components of the autism spectrum : a twin study", J. Am. Acad. Child Adolesc. Psychiatry, 45, pp.691~699 (2006)
- Gaugler, T., "Most genetic risk for autism resides with common variation", Nat Genet, 46, pp.881~ (2014)
- Bai, D., "Association of genetic and environmental factors with autism in a 5-country cohort", JAMA Psychiatry, 76, pp.1035~1043 (2019)
- Iossifov, I., "The contribution of de novo coding mutations to autism spec trum disorder", Nature, 515, pp.216~ (2014)
- Krumm, N., "Excess of rare, inherited truncating mutations in autism", Nat. Genet, 47, pp.582~ (2015)
- Gratten, J., "Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease", Nat. Genet, 45, pp.234~ (2013)
- De Rubeis, S., "Synaptic, transcriptional and chromatin genes disrupted in autism", Nature, 515, pp.209~ (2014)
- O’Roak, B. J., "Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations", Nat. Genet, 43, pp.585~ (2011)
- Lim, E. T., "Rates, distribution and implications of postzygotic mosaic muta tions in autism spectrum disorder", Nat. Neurosci, 20, pp.1217~ (2017)
- Poduri, A., "Somatic mutation, genomic var iation, and neurological disease", Science, 341, pp.1237758~ (2013)[DOI]
- Lee, J. H., "Somatic mutations in disorders with disrupted brain connectivity", Exp. Mol. Med, 48, pp.e239~ (2016)[DOI]
- Lim, J. S., "Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy", Nat. Med, 21, pp.395~400 (2015)[DOI]
- Pelorosso, C., "Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy", Hum. Mol. Genet (2019)[DOI]
- Sim, N. S., "Precise detection of low-level somatic mutation in resected epilepsy brain tissue", Acta Neuropathol, 138, pp.901~912 (2019)
- Kim, M. -H., "Low-level brain somatic mutations are implicated in schizo phrenia", Biol. Psychiatry, 90, pp.35~46 (2021)
- Park, J. S., "Brain somatic mutations observed in Alzheimer’s disease asso ciated with aging and dysregulation of tau phosphorylation", Nat. Commun, 10, pp.3090~ (2019)
- D’Gama, A. M., "Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms", Neuron, 88, pp.910~917 (2015)
- Freed, D., "The contribution of mosaic variants to autism spectrum disorder", PLoS Genet, 12, pp.e1006245~ (2016)
- Rodin, R. E., "The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing", Nat. Neurosci, 24, pp.176~185 (2021)
- Sherman, M. A., "Large mosaic copy number variations confer autism risk", Nat. Neurosci, 24, pp.197~203 (2021)
- Cibulskis, K., "Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples", Nat. Biotechnol, 31, pp.213~ (2013)
- Kim, J., "The use of technical replication for detection of low-level somatic mutations in next-generation sequencing", Nat. Commun, 10, pp.1047~ (2019)
- Cibulskis, K., "ContEst : estimating cross-contamination of human samples in next-generation sequencing data", Bioinformatics, 27, pp.2601~2602 (2011)[DOI]
- Shiraishi, Y., "An empirical Bayesian framework for somatic mutation detec tion from cancer genome sequencing data", Nucleic Acids Res, 41, pp.e89~e89 (2013)
- Thorvaldsdóttir, H., "Integrative Genomics Viewer(IGV) : high-performance genomics data visualization and exploration", Brief Bioinforma, 14, pp.178~192 (2013)
- Abrahams, B. S., "SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)", Mol. Autism, 4, pp.36~ (2013)[DOI]
- Kuleshov, M. V., "Enrichr : a comprehensive gene set enrichment analysis web server 2016 update", Nucleic Acids Res, 44, pp.W90~W97 (2016)[DOI]
- Lee, J., "Mutalisk : a web-based somatic MUTation AnaLyIS toolKit for geno mic, transcriptional and epigenomic signatures", Nucleic Acids Res, 46, pp.W102~W108 (2018)[DOI]
- Calderone, A., "Mentha : a resource for browsing integrated protein-interaction networks", Nat Methods, 10, pp.690~ (2013)
- Shohat, S., "Varying intolerance of gene pathways to mutational classes explain genetic convergence across neuropsychiatric dis orders", Cell Rep, 18, pp.2217~2227 (2017)
- Kang, H. J., "Spatio-temporal transcriptome of the human brain", Nature, 478, pp.483~ (2011)
- Krishnan, A., "Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder", Nat. Neurosci, 19, pp.1454~ (2016)
- Kim, J. H., "Analysis of low-level somatic mosaicism reveals stage and tissue specific mutational features in human development", PLoS Genet, 18, pp.e1010404~ (2022)[DOI]
- Rahbari, R., "Timing, rates and spectra of human germline mutation", Nat. Genet, 48, pp.126~133 (2016)[DOI]
- Goldmann, J. M., "Parent-of-origin-specific signatures of de novo mutations", Nat. Genet, 48, pp.935~939 (2016)[DOI]
- McLaren, W., "The Ensembl Variant Effect Predictor", Genome Biol, 17, pp.122~ (2016)[DOI]
- Samocha, K. E., "A framework for the interpretation of de novo mutation in human disease", Nat. Genet, 46, pp.944~ (2014)
- Karczewski, K. J., "The mutational constraint spectrum quantified from var iation in 141, 456 humans", Nature, 581, pp.434~443 (2020)
- Rentzsch, P., "CADD: predicting the deleteriousness of variants throughout the human genome", Nucleic Acids Res, 47, pp.D886~D894 (2019)[DOI]
- Pinto, D., "Convergence of genes and cellular pathways dysregulated in autism spectrum disorders", Am. J Hum. Genet, 94, pp.677~694 (2014)
- Iwamoto, T., "Motor dysfunction in type 5 adenylyl cyclase-null mice", J Biol Chem, 278, pp.16936~16940 (2003)[DOI]
- Carapito, R., "A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia", Mov. Disord, 30, pp.423~427 (2015)[DOI]
- Bond, J., "A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size", Nat Genet, 37, pp.353~ (2005)
- Long, J., "Expanded characterization of the social interaction abnormalities in mice lacking Dvl1", Genes, Brain Behav, 3, pp.51~62 (2004)
- Moy, S. S., "Deficient NRG1-ERBB signaling alters social approach : relevance to genetic mouse models of schizophrenia", J Neurodev. Disord, 1, pp.302~ (2009)
- Stewart, A., "Regulator of G-protein signaling 6(RGS6)promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor adenylyl cyclase axis", FASEB J, 28, pp.1735~1744 (2014)
- Coban-Akdemir, Z., "Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles", Am. J Hum. Genet, 103, pp.171~187 (2018)[DOI]
- McKenzie, A. T., "Brain cell type specific gene expression and co-expression network architectures", Sci. Rep, 8, pp.1~19 (2018)
- Turner, T. N., "Genomic patterns of de novo mutation in simplex autism", Cell, 171, pp.710~722 (2017)
- RK, C. Y., "Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder", Nat. Neurosci, 20, pp.602~611 (2017)[DOI]
- Yuen, R. K., "Genome-wide characteristics of de novo mutations in autism", NPJ Genom. Med, 1, pp.16027~ (2016)
- Ding, J., "Systematic analysis of somatic mutations impacting gene expres sion in 12 tumour types", Nat. Commun, 6, pp.8554~ (2015)[DOI]
- Courchesne, E., "Mapping early brain development in autism", Neuron, 56, pp.399~413 (2007)[DOI]
- Masuda, F., "Motor cortex excitability and inhibitory imbalance in autism spec trum disorder assessed with transcranial magnetic stimulation : a systematic review", Transl. Psychiatry, 9, pp.110~ (2019)[DOI]
- Khan, S., "Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale", Brain, 138, pp.1394~1409 (2015)[DOI]
- Tomasi, D., "Reduced local and increased long-range functional connectivity of the thalamus in autism spectrum disorder", Cereb. Cortex, 29, pp.573~585 (2019)[DOI]
- Schuetze, M., "Morphological alterations in the thalamus, striatum, and pal lidum in autism spectrum disorder", Neuropsychopharmacology, 41, pp.2627~2637 (2016)[DOI]
- Dougherty, J. D., "Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells", Nucleic Acids Res, 38, pp.4218~4230 (2010)[DOI]
- Zikopoulos, B., "Changes in prefrontal axons may disrupt the network in autism", J. Neurosci, 30, pp.14595~14609 (2010)
- Xu, Q., "Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons", Mol. Autism, 9, pp.65~ (2018)[DOI]
- Lazar, M., "Axonal deficits in young adults with High Functioning Autism and their impact on processing speed", Neuro Image : Clin, 4, pp.417~425 (2014)
- Martínez-Cerdeño, V., "Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models", Dev. Neurobiol, 77, pp.393~404 (2017)
- Gouder, L., "Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations", Sci. Rep, 9, pp.94~ (2019)[DOI]
- Willsey, A. J., "Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism", Cell, 155, pp.997~1007 (2013)[DOI]
- Gargus, J. J., "Genetic calcium signaling abnormalities in the central nervous sys tem: seizures, migraine, and autism", Ann. N. Y. Acad. Sci, 1151, pp.133~156 (2009)[DOI]
- Abekhoukh, S., "CYFIP family proteins between autism and intellec tual disability: links with Fragile X syndrome", Front. Cell Neurosci, 8, pp.81~ (2014)[DOI]
- van Bon, B. W., "Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID", Mol. Psychiatry, 21, pp.126~132 (2016)[DOI]
- Langridge, A. T., "Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability", PLoS One, 8, pp.e50963~ (2013)[DOI]
- Guilmatre, A., "Recurrent rearrangements in synaptic and neurodevelop mental genes and shared biologic pathways in schizophrenia, autism, and mental retardation", Arch. Gen. Psychiatry, 66, pp.947~956 (2009)[DOI]
- Berkel, S., "Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation", Nat. Genet, 42, pp.489~491 (2010)[DOI]
- Alesi, V., "335.4 kb microduplication in chromosome band Xp11.2p11.3associated with developmental delay, growth retardation, autistic disorder and dysmorphic features", Gene, 505, pp.384~387 (2012)[DOI]
- Pyhälä, R., "Very low birth weight, infant growth, and autism-spectrum traits in adulthood", Pediatrics, 134, pp.1075~1083 (2014)
- Lampi, K. M., "Risk of autism spectrum disorders in low birth weight and small for gestational age infants", J. Pediatr, 161, pp.830~836 (2012)[DOI]
- Werling, D. M., "Whole-Genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex", Cell Rep, 31, pp.107489~ (2020)[DOI]
- delaTorre-Ubieta, L., "Advancingtheunder standing of autism disease mechanisms through genetics", Nat. Med, 22, pp.345~ (2016)
- Lee, K. W., "Impaired D2 dopamine receptor function in mice lacking type 5adenylyl cyclase", J Neurosci, 22, pp.7931~7940 (2002)
- Garcez, P. P., "Cenpj", CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of Ascl1, 2015, pp.6, 6474~
- Rosso, S. B., "Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development", Nat. Neurosci, 8, pp.34~ (2005)
- Rosso, S. B., "WNT signaling in neuronal maturation and synap togenesis", Front. Cell Neurosci, 7, pp.103~ (2013)
- Mahar, I., "Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects", PLoS One, 6, pp.e26610~ (2011)[DOI]
- Mahar, I., "Effects of neuregulin-1 administration on neurogenesis in the adult mouse hippocampus, and characterization of immature neurons along the sep totemporal axis", Sci. Rep, 6, pp.30467~ (2016)[DOI]
- Luo, Z., "Regulator of G protein Signaling 6 (RGS6) suppresses late-age-onset Nigral Dopaminergic Neurodegeneration, α-Synuclein accumulation and motor dysfunction", FASEB J, 33, pp.669~ (2019)
- Bristow, J. M., "Dynamic phos phorylation of tyrosine 665 in pseudopodium-enriched atypical kinase 1(PEAK1)is essential for the regulation of cell migration and focal adhesion turnover", J. Biol. Chem, 288, pp.123~131 (2013)
- Reiner, O., "Regulation of neuronal migration, an emerging topic in autism spectrum disorders", J. Neurochem, 136, pp.440~456 (2016)
- Wegiel, J., "The neuropathology of autism : defects of neurogenesis and neuronal migration, and dysplastic changes", Acta. Neuropathol, 119, pp.755~770 (2010)
- Goubert, E., "Inhibition of the mitochondrial glutamate carrier SLC25A22 in astrocytes leads to intracellular glutamate accumulation", Front Cell Neurosci, 11, pp.149~ (2017)[DOI]
- Napolioni, V., "The mitochondrial aspartate", glutamate carrier AGC1 and calcium homeostasis: physiological links and abnormalities in autism, 2011, pp.44, 83~92
- Wang, Z., "A small change in neuronal network topology can induce explosive synchronization transition and activity propaga tion in the entire network", Sci. Rep, 7, pp.561~ (2017)
- Petrelli, F., "Astrocytes and microglia and their potential link with autism spectrum disorders", Front Cell Neurosci, 10, pp.21~ (2016)
- Shi, W., "Reliability of whole-exome sequencing for assessing intratumor genetic heterogeneity", Cell Rep, 25, pp.1446~1457 (2018)[DOI]
- Guo, H., "Inherited and multiple de novo mutations in autism", developmental delay risk genes suggest a multifactorial model, 2018, pp.9, 64~
- Pinero, J., "DisGeNET : a comprehensive platform integrating information on human disease-associated genes and variants", Nucleic Acids Res, 45, pp.D833~D839 (2017)[DOI]
- The Gene Ontology, C, "The Gene Ontology Resource: 20 years and still GOing strong", Nucleic Acids Res, 47, pp.D330~D338 (2019)[DOI]
- Kohler, S., "Expansion of the Human Phenotype Ontology(HPO)knowledge base and resources", Nucleic Acids Res, 47, pp.D1018~D1027 (2019)[DOI]
