Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process “skiagenesis” (from the Greek skia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (∼13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes. Skiagenesis provides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.

[1]  Colin M. Diesh,et al.  CNVpytor: a tool for copy number variation detection and analysis from read depth and allele imbalance in whole-genome sequencing , 2021, GigaScience.

[2]  E. M. DeGennaro,et al.  Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions , 2021, Neuron.

[3]  K. Ligon,et al.  Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain , 2021, Cancer discovery.

[4]  Nicholette D. Palmer,et al.  Population sequencing data reveal a compendium of mutational processes in human germline , 2021, Science.

[5]  C. Walsh,et al.  Landmarks of human embryonic development inscribed in somatic mutations , 2021, Science.

[6]  P. García,et al.  Persistence of RNA transcription during DNA replication delays duplication of transcription start sites until G2/M , 2021, Cell reports.

[7]  Sara B. Linker,et al.  The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing , 2021, Nature Neuroscience.

[8]  Hannes P. Eggertsson,et al.  Differences between germline genomes of monozygotic twins , 2021, Nature Genetics.

[9]  A. Gonzalez-Perez,et al.  Variable interplay of UV-induced DNA damage and repair at transcription factor binding sites , 2020, Nucleic acids research.

[10]  Peter J. Park,et al.  Comprehensive identification of somatic nucleotide variants in human brain tissue , 2020, bioRxiv.

[11]  S. Ripke,et al.  Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia , 2020, medRxiv.

[12]  A. Bernabé-Ortiz,et al.  A systematic review of population-based studies on lipid profiles in Latin America and the Caribbean , 2020, eLife.

[13]  E. Heinzen.  Somatic variants in epilepsy - advancing gene discovery and disease mechanisms. , 2020, Current opinion in genetics & development.

[14]  M. Perez,et al.  An International Multicenter Evaluation of Type 5 Long QT Syndrome , 2020, Circulation.

[15]  M. Fullwood,et al.  H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions , 2019, Nature Communications.

[16]  Yongxia Huo,et al.  Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk , 2019, Nature Communications.

[17]  Ryan L. Collins,et al.  Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes , 2019, bioRxiv.

[18]  V. Makeev,et al.  Genome-wide map of human and mouse transcription factor binding sites aggregated from ChIP-Seq data , 2018, BMC Research Notes.

[19]  C. Walsh,et al.  Somatic Mutation in Pediatric Neurological Diseases. , 2018, Pediatric neurology.

[20]  Steven A Roberts,et al.  ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma , 2018, Nature Communications.

[21]  W. Reik,et al.  Dynamics of the epigenetic landscape during the maternal-to-zygotic transition , 2018, Nature Reviews Molecular Cell Biology.

[22]  R. Lifton,et al.  Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis , 2018, Human Genome Variation.

[23]  Ville Mustonen,et al.  The repertoire of mutational signatures in human cancer , 2018, Nature.

[24]  Bo-Juen Chen,et al.  Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis , 2018, Science.

[25]  Arthur W. Toga,et al.  Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data Across 27 Tissue Types , 2018, bioRxiv.

[26]  L. Jansen.  The Space-Time Continuum of Cortical Dysplasia , 2017, Cell reports.

[27]  Mauricio O. Carneiro,et al.  Scaling accurate genetic variant discovery to tens of thousands of samples , 2017, bioRxiv.

[28]  E. Cuppen,et al.  MutationalPatterns: comprehensive genome-wide analysis of mutational processes , 2017, bioRxiv.

[29]  Hyunju Kim,et al.  Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring , 2017, Nature.

[30]  Ian R. Wickersham,et al.  Reversing behavioral abnormalities in mice exposed to maternal inflammation , 2017, Nature.

[31]  Christopher S. Poultney,et al.  Rates, Distribution, and Implications of Post-zygotic Mosaic Mutations in Autism Spectrum Disorder , 2017, Nature Neuroscience.

[32]  A. Y. Ye,et al.  Postzygotic single‐nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations , 2017, Human mutation.

[33]  Yi Zhang,et al.  TET-mediated active DNA demethylation: mechanism, function and beyond , 2017, Nature Reviews Genetics.

[34]  Wei Cheng,et al.  Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects , 2016, Nature Genetics.

[35]  B. O’Roak,et al.  Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder , 2016, bioRxiv.

[36]  G. Cooper,et al.  Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy , 2016, Neurology: Genetics.

[37]  A. McAllister,et al.  Maternal immune activation: Implications for neuropsychiatric disorders , 2016, Science.

[38]  Beth K. Martin,et al.  Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. , 2016, JAMA neurology.

[39]  Jeong Ho Lee.  Somatic mutations in disorders with disrupted brain connectivity , 2016, Experimental & Molecular Medicine.

[40]  Anushi Shah,et al.  Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes , 2016, Nature.

[41]  N. Šestan,et al.  The Cellular and Molecular Landscapes of the Developing Human Central Nervous System , 2016, Neuron.

[42]  Radhakrishnan Sabarinathan,et al.  Nucleotide excision repair is impaired by binding of transcription factors to DNA , 2015, Nature.

[43]  B. L. Caputto,et al.  Brain development is impaired in c-fos −/− mice , 2015, Oncotarget.

[44]  Niko Välimäki,et al.  CTCF/cohesin-binding sites are frequently mutated in cancer , 2015, Nature Genetics.

[45]  Kristian Vlahovicek,et al.  Genomation: a Toolkit to Summarize, Annotate and Visualize Genomic Intervals , 2015, Bioinform..

[46]  Seok-Gu Kang,et al.  Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy , 2015, Nature Medicine.

[47]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[48]  D. Gordenin,et al.  The choice of nucleotide inserted opposite abasic sites formed within chromosomal DNA reveals the polymerase activities participating in translesion DNA synthesis. , 2013, DNA repair.

[49]  Matthew D. Shirley,et al.  Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. , 2013, The New England journal of medicine.

[50]  B. Faircloth,et al.  Primer3—new capabilities and interfaces , 2012, Nucleic acids research.

[51]  G. Lewis,et al.  Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies , 2012, Psychological Medicine.

[52]  Alan S. Brown,et al.  Maternal infection and schizophrenia: implications for prevention. , 2011, Schizophrenia bulletin.

[53]  T. Paunio,et al.  Findings from bipolar disorder genome-wide association studies replicate in a Finnish bipolar family-cohort , 2009, Molecular Psychiatry.

[54]  P. Chambon,et al.  A transcriptionally silent RXRα supports early embryonic morphogenesis and heart development , 2009, Proceedings of the National Academy of Sciences.

[55]  H. Lachman.  Copy variations in schizophrenia and bipolar disorder , 2009, Cytogenetic and Genome Research.

[56]  Susanne Walitza,et al.  Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies , 2008, Journal of Neural Transmission.

[57]  S. Akbarian,et al.  Neuronal nuclei isolation from human postmortem brain tissue. , 2008, Journal of visualized experiments : JoVE.

[58]  S. Cichon,et al.  A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder , 2008, Molecular Psychiatry.

[59]  Maido Remm,et al.  Enhancements and modifications of primer design program Primer3 , 2007, Bioinform..

[60]  Frank Grosveld,et al.  Transcription Factor Sp1 Is Essential for Early Embryonic Development but Dispensable for Cell Growth and Differentiation , 1997, Cell.

[61]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..